A Phase 1 interventional study of Ertapenem and Placebo in Bacterial Infection, sponsored by National Institute of Allergy and Infectious Diseases (NIAID). Completed at 1 site in United States. Open to participants aged 18 Years to 45 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2025-01-20.
Sponsored by National Institute of Allergy and Infectious Diseases (NIAID) · Phase 1, Interventional, and Treatment
This is a Phase 1, single center study to investigate the safety, tolerability, and pharmacokinetics (PK) of three dose-level groups of WCK 6777 (ERT and ZID combination), and two dose-level groups of ERT alone and ZID (WCK 5107) alone in 52 healthy adult male and female subjects aged 18 to 45 years old (both inclusive). Seven treatment cohorts will be evaluated in this study. WCK 6777 will be evaluated in three cohorts - Cohorts 1, 4 and 7- of 8 subjects each (6 study drug combinations and 2 placebos); ERT will be evaluated alone in two cohorts - Cohorts 2 and 5- of 8 subject each (6 ERT and 2 placebos); and ZID will be evaluated in two cohorts, Cohorts 3 and 6, of 6 subjects each (all ZID). The study will be placebo-controlled and double-blinded in all cohorts except Cohorts 3 and 6. No placebo subjects are included in standalone ZID cohorts, since adequate safety data for higher doses of ZID alone in comparison with placebo are available from completed Phase 1 studies of WCK 5107 (ZID) alone and the ZID-only arms of WCK 5222 (cefepime + ZID) studies. The primary objective is to assess the safety and tolerability of three dose-escalating regimens of WCK 6777 ( ERT and ZID combination) and two-dose escalating regimens of standalone ERT or ZID following single daily doses for 7 days in healthy adult subjects.
This is a Phase 1, single center study to investigate the safety, tolerability, and pharmacokinetics (PK) of three dose-level groups of WCK 6777 (ERT and ZID combination), and two dose-level groups of ERT alone and ZID (WCK 5107) alone in 52 healthy adult male and female subjects aged 18 to 45 years old (both inclusive). Seven treatment cohorts will be evaluated in this study. WCK 6777 will be evaluated in three cohorts - Cohorts 1, 4 and 7- of 8 subjects each (6 study drug combinations and 2 placebos); ERT will be evaluated alone in two cohorts - Cohorts 2 and 5- of 8 subject each (6 ERT and 2 placebos); and ZID will be evaluated in two cohorts, Cohorts 3 and 6, of 6 subjects each (all ZID). The study will be placebo-controlled and double-blinded in all cohorts except Cohorts 3 and 6. No placebo subjects are included in standalone ZID cohorts, since adequate safety data for higher doses of ZID alone in comparison with placebo are available from completed Phase 1 studies of WCK 5107 (ZID) alone and the ZID-only arms of WCK 5222 (cefepime + ZID) studies. In each cohort, either study drugs alone or their combination will be administered by a single intravenous infusion (IV) of 100 mL daily for 7 consecutive days in Cohort 1 or 250 mL daily for 7 consecutive days in Cohorts 2 to 7. For each treatment cohort, however, the dose will be progressively escalated from 1 g/daily to 2 g/daily and to 3 g/daily, and the duration of infusion time increased from 30 min to 1 h and to 2 h over the course of the study. In Cohort 1, WCK 6777 2 g (ERT 1 g/daily combined with ZID 1 g/daily) will be administered in 30 (±5) minutes (min); in Cohort 2 (ERT 2 g/daily), Cohort 3 (ZID 2 g/daily), and Cohort 4 (WCK 6777 4 g [ERT 2 g/daily combined with ZID 2 g/daily]) the study drug(s) will be administered in 60 (±10) min, and in Cohort 5 (ERT 3 g/daily), Cohort 6 (ZID 3 g daily) and Cohort 7 (WCK 6777 6 g [ERT 3 g/daily combined with ZID 3 g/daily]), the study drug(s) will be administered in 120 (±10) min. The primary objective is to assess the safety and tolerability of three dose-escalating regimens of WCK 6777 ( ERT and ZID combination) and two-dose escalating regimens of standalone ERT or ZID following single daily doses for 7 days in healthy adult subjects. The secondary objective is to characterize the PK profiles in plasma (total \& free) and in urine of three dose-escalating regimens of WCK 6777 (ERT and ZID combination) and two dose-escalating regimens of standalone ERT or ZID following a single initial dose on Day 1 and after single daily doses for 7 days in healthy adult subjects.
658 studies on the registry are indexed under Bacterial Infections; 100 are open to participants now.
This study's enrollment of 54 is below the median of 84 across 405 interventional studies indexed under Bacterial Infections.
Browse Bacterial Infections studies →National Institute of Allergy and Infectious Diseases (NIAID) is the lead sponsor of 2,401 studies on the registry; 179 are open to participants now.
Of its 396 completed or terminated interventional studies of FDA-regulated products, 294 (74%) have results posted.
Counted across the registry records on this site, refreshed daily.
Be in good general health at the time of enrollment. Note 1: Determined by medical history (MH), medication use, physical examination (PE), vital signs (VS), clinical laboratory tests including estimated creatinine clearance (CLCR) > / = 80 mL/min by the Cockcroft-Gault method, and 12-lead Electrocardiogram (ECG) within reference ranges at Screening and Day-1.
Note 2: Exceptions to Blood Pressure (BP), Heart Rate (HR) and laboratory test values being with normal ranges are:
Sexually active females must be of non-childbearing potential or must use a highly effective method of birth control from screening to 30 days following the last dose of study product.
Note 1: A female is considered of childbearing potential unless post-menopausal (defined as history of > / = 1 year of spontaneous amenorrhea and a Follicle-Stimulating Hormone (FSH) level >40 IU/L), or permanently surgically sterilized.
Note 2: Highly effective contraceptive methods include: (a) surgical sterilization methods, such as tubal ligation, bilateral oophorectomy, salpingectomy, hysterectomy, or successful tubal obliteration (e.g., Essure(R)) with documented radiological confirmation test at least 90 days after the procedure, or (b) long-acting reversible contraception, such as progestin-releasing subdermal implants, copper intrauterine devices (IUDs), levonorgestrel-releasing IUDs.
Note 3: A subject who is not sexually active and abstains from sexual intercourse can be enrolled and abstinence documented.
Sexually active males must be vasectomized or agree to use barrier contraception and not donate sperm from first dose of study product until 30 days following the last dose.
Note 1: Barrier contraception includes use of condom with spermicide. Note 2: A subject who is not sexually active and abstains from sexual intercourse can be enrolled and abstinence documented.
Exclusion Criteria:
Any history of a chronic condition including renal failure that may increase risk to subject or interfere with endpoint assessment, or any unstable chronic disease.
Note 1: Unstable chronic disease is defined by need for frequent medical interventions that lead to a change in medications and/or required hospitalization, surgery or an invasive procedure or emergency department/urgent care visit, as determined by the Site PI.
Note 2: Any chronic disease, that has been diagnosed within 90 days of screening is excluded.
History of > / = 10 pack-years smoking in the 5-year period before screening, or positive urine cotinine screen at check-in.
Note 1: Nicotine products include cigarettes, e-cigarettes, pipe, cigar, chewing tobacco, nicotine patch.
Note 2: Positive urine cotinine at screening is allowed if negative at check-in (Day -1).
Note 1: Binge drinking is defined as 5 or more drinks during single occasion if male, or 4 or more if female.
Note 2: Heavy drinking of alcohol is defined as consumption of more than 15 units of alcohol per week if male, or more than 8 units if female.
WCK 6777 (Ertapenem 1 g combined with Zidebactam 1 g) or placebo administered by 100 ml of intravenous infusion (IV) for 30 (±5) minutes once daily for 7 days. N= 8
Drug: Ertapenem · Other: Placebo · Drug: WCK 6777 · Drug: Zidebactam
Ertapenem 2 g or placebo administered by 250 ml of intravenous infusion (IV) for 1 hour once daily for 7 days. N=8
Drug: Ertapenem · Other: Placebo
Zidebactam 2 g administered by 250 ml of intravenous infusion (IV) for 1 hour,once daily,for 7 days. N=6
Drug: Zidebactam
WCK 6777 (Ertapenem 2 g combined with Zidebactam 2 g) or placebo administered by 250 ml of intravenous infusion (IV) for 1 hour, once daily, for 7 days. N=8
Drug: Ertapenem · Other: Placebo · Drug: WCK 6777 · Drug: Zidebactam
Ertapenem 3 g or placebo administered by 250 ml of intravenous infusion (IV) for 2 hours, once daily, for 7 days. N=8
Drug: Ertapenem · Other: Placebo
Zidebactam 3 g administered by 250 ml of intravenous infusion (IV) for 2 hours, once daily, for 7 days. N=6
Drug: Zidebactam
WCK 6777 (Ertapenem 3 g combined with Zidebactam 3 g) or placebo administered by 250 ml of intravenous infusion (IV) for 2 hours, once daily, for 7 days. N=8
Drug: Ertapenem · Other: Placebo · Drug: WCK 6777 · Drug: Zidebactam
A 1-beta methyl-carbapenem that is structurally related to beta-lactam antibiotics
Placebo
A combination of ertapenem (ERT) and zidebactam (ZID)
A betaß-lactamase inhibitor and betaß-lactam enhancer from the diazabicyclooctane (DBO) class
Number of Participants With Treatment-Emergent Adverse Events
Adverse events (AEs) are defined as any untoward medical occurrence in a participant or clinical investigation participant who was administered a pharmaceutical product, regardless of its causal relationship to the product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of the product, and are described as treatment-emergent AEs (TEAEs). Number of participants with a TEAE are summarized by dose group and by MedDRA System Organ Class (SOC).
Time frame: Day 1 through Day 11
Number of Treatment-Emergent Adverse Events Reported
Adverse events (AEs) are defined as any untoward medical occurrence in a participant or clinical investigation participant who was administered a pharmaceutical product, regardless of its causal relationship to the product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of the product, and are described as treatment-emergent AEs (TEAEs). Number of TEAEs reported are summarized by dose group and MedDRA System Organ Class (SOC)..
Time frame: Day 1 through Day 11
Number of Participants With Treatment-Emergent Adverse Events Related to Study Product
Adverse events (AEs) are defined as any untoward medical occurrence in a participant or clinical investigation participant who was administered a pharmaceutical product, regardless of its causal relationship to the product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of the product, and are described as treatment-emergent AEs (TEAEs). TEAEs are assessed by the investigator to determine relationship to the study drug. Number of participants with a related TEAE are summarized by dose group and by MedDRA System Organ Class (SOC).
Time frame: Day 1 through Day 11
Number of Serious Adverse Events Reported
Serious AEs (SAEs) meet one or more of the following criteria: death, life-threatening AEs, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, substantial disruption of the ability to conduct normal life function, congenital anomaly/birth defect, or important medical events that may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. SAEs are listed.
Time frame: Day 1 through Day 11
Number of Participants With Abnormal Chemistry Laboratory Toxicity Results
Parameters and thresholds include alanine aminotransferase =33 (female (F) 19Y), =30 (F \>19) or =47 U/L (male (M) =19Y); albumin =3.5 g/dL; alkaline phosphatase =129 (F 19Y), =126 (F =49Y), =170 (M 19Y) or =131 U/L (M =49Y); aspartate aminotransferase =33 (19Y) or =41 U/L (20-49Y); bilirubin =1.2 (19Y) or =1.3 mg/dL (\>19Y); calcium =8.8 (4-19Y), =8.5 (20-49Y), =10.5 (4-19Y), =10.3 (F 20-49Y) or =10.4 mg/dL (M 20-49Y); carbon dioxide =19 or =33 mmol/L; creatinine =0.97 (F 18-29Y), =0.98 (F 30-39Y), =1.00 (F 40-49Y), =1.25 (M 18-29Y), =1.27 (M 30-39Y) or =1.30 mg/dL (M 40-49Y); direct bilirubin =0.3 mg/dL; glucose =64 or =100 mg/dL; potassium =3.7 (19Y), =3.4 (\>19Y), = 5.2 (19Y) or = 5.4 mmol/L (\>19Y); protein =6.2 (19Y) or =6.0 g/dL (\>19Y); sodium =134 or =147 mmol/L; and urea nitrogen =21 (19Y) or =26 mg/dL (\>19Y). All abnormal toxicity results are included, but Grade 1 values at screening/baseline allowed for enrollment were only considered TEAEs if they increased in severity.
Time frame: Day 1 through Day 11
Number of Participants With Abnormal Hematology Laboratory Toxicity Results
Parameters and thresholds include basophils =201 x106/L (\>6Y); eosinophils =501 x106/L (\>6Y); hemoglobin =11.4 (female (F) 18Y), =11.6 (F \>18Y), =11.9 (male (M) 18Y) or =13.1 g/dL (M \>18Y); leukocytes =4.4 (18Y), =3.7 (\>18Y), =13.1 (18Y) or =10.9 x109/L (\>18Y); lymphocytes =1199 (18Y) or =849 x106/L (\>18Y); monocytes =901 (18Y) or =951 x106/L (\>18Y); neutrophils =1799 (18Y) or =1499 x106/L (\>18Y); and platelets \<140 x109/L. All abnormal toxicity results are included, but Grade 1 values at screening/baseline allowed for enrollment were only considered TEAEs if they increased in severity.
Time frame: Day 1 through Day 11
Number of Participants With Abnormal Coagulation Laboratory Toxicity Results
Parameters and thresholds include activated partial thromboplastin time \>32 s, prothrombin intl. normalized ratio \>1.1 (ratio), and prothrombin time \>11.5 s. All abnormal toxicity results are included, but Grade 1 values at screening/baseline allowed for enrollment were only considered TEAEs if they increased in severity.
Time frame: Day 1 through Day 11
Number of Participants With Abnormal Urinalysis Laboratory Toxicity Results
Parameters and thresholds include dipstick measurements of glucose =1+, leukocyte esterase =1+, occult blood =1+, protein =1+ and urinalysis with microscopy results of at least a few bacteria, red blood cells (RBC) =3 per high-powered field (HPF), and white blood cells (WBC) =6 per HPF. If dipstick results were abnormal, urinalysis with microscopy was performed. All abnormal toxicity results are included, but Grade 1 values at screening/baseline allowed for enrollment were only considered TEAEs if they increased in severity.
Time frame: Day 1 through Day 11
Number of Participants With Abnormal Electrocardiogram (ECG) Toxicity Results
The only ECG parameters graded were PR interval with a threshold of =211 msec and QTcF interval with a threshold of =471 msec (female) or =451 msec (male) or an increase of =30 msec above baseline. ECG values after dosing were considered as TEAEs if they met toxicity grading criteria.
Time frame: Day 8 and Day 11
Number of Participants With Abnormal Vital Signs (VS)
VS parameters and thresholds include diastolic blood pressure =90 mmHg, oral temperature =37.3 °C, pulse =49 or =101 beats/min, respiratory rate =21 breaths/min, and systolic blood pressure =88 or =131 mmHg. VS could be repeated up to twice more at rest and within at least 5 minutes of each other. The following rules were used to determine which vital sign measurement to use for analysis if repeat measurements occurred: 1. If the first replicate was normal, it was used. 2. If the first and second replicates were both abnormal, the replicate with the higher severity was used. 3. If the first replicate was abnormal, the second replicate was normal, and the third replicate was not performed, the first replicate was used. 4. If the first replicate was abnormal and the second and third replicates were normal, the second replicate was used. 5. If the first and third replicates were abnormal and the second replicate was normal, the abnormal replicate with the higher severity was used.
Time frame: Day 1 through Day 11
Maximum Observed Concentration (Cmax) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the Cmax (µg/mL) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group.
Time frame: =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion
Minimum Observed Concentration (Cmin) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the Cmin (µg/mL) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group.
Time frame: =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion
Predicted Concentration at the End of the Dosing Interval (Ctau) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the Ctau (µg/mL) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group. Ctau is estimated using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
Time frame: =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion
Dose-Normalized Maximum Observed Concentration (Cmax/Dose) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the dose-normalized Cmax ((µg/mL)/mg) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group
Time frame: =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion
Time of Maximum Concentration (Tmax) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Median and minimum/maximum of the Tmax (h) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group.
Time frame: =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion
Time of Minimum Concentration (Tmin) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Median and minimum/maximum of the Tmin (h) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group.
Time frame: =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion
Area Under the Concentration-Time Curve From Dosing to the Predicted Time the Concentration Reaches the Lower Limit of Quantification (AUC(0-t)) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the total area under the concentration-time curve from dosing (time 0 h) extrapolated to the time the concentration is predicted to reach the lower limit of quantification (LLOQ), AUC(0-t) (µg\*h/mL), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
Time frame: =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion
Area Under the Concentration-Time Curve From Dosing to Time of the Last Measured Concentration (AUC(0-last)) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the total area under the concentration-time curve from dosing (time 0 h) to the time of last measured concentration, AUC(0-last) (µg\*h/mL),parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group.
Time frame: =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion
Area Under the Concentration-Time Curve From Dosing Taken to the Limit as the End Time Becomes Arbitrarily Large (AUC(0-inf)) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the total area under the concentration-time curve from dosing (time 0 h) taken to the limit as the end time becomes arbitrarily large, AUC(0-inf) (µg\*h/mL), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
Time frame: =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion
Area Under the Concentration-Time Curve From Dosing Extrapolated to 24 Hours After Dosing (AUC(0-24)) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the total area under the concentration-time curve from dosing (time 0 h) extrapolated to 24 h after dosing, AUC(0-24) (µg\*h/mL), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
Time frame: =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion
Area Under the Concentration-Time Curve From Dosing to the End of the Dosing Interval (AUC(0-tau)) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the total area under the concentration-time curve from dosing (time 0 h) to the end of the dosing interval (24 h post-infusion), AUC(0-tau) (µg\*h/mL), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration
Time frame: =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion
Dose-Normalized Area Under the Concentration-Time Curve From Dosing to the End of the Dosing Interval (AUC(0-tau)/Dose) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the dose-normalized total area under the concentration-time curve from dosing (time 0 h) to the end of the dosing interval (24 h post-infusion), AUC(0-tau)/Dose ((µg\*h/mL)/mg), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
Time frame: =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion
Terminal Elimination Half-Life (t1/2) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the terminal elimination half-life, t1/2 (h), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
Time frame: =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion
Total Clearance (CLT) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the total clearance, CLT (L/h), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
Time frame: =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion
First-Order Terminal Phase Elimination Rate Constant (Ke) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the first-order terminal phase elimination rate constant, Ke (1/h), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
Time frame: =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion
Apparent Volume of Distribution (Vd) for Dose 1 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the apparent volume of distribution, Vd (L), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
Time frame: =0.5 h prior to dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) infusion
Maximum Observed Concentration at Steady State (Cmax,ss) of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the Cmax,ss (µg/mL) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group. These estimates assume steady state has been achieved.
Time frame: =0.5 h prior to the start of Dose 7 (Day 7) dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 7 infusion
Minimum Observed Concentration at Steady State (Cmin,ss) of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the Cmin,ss (µg/mL) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group. These estimates assume steady state has been achieved.
Time frame: =0.5 h prior to the start of Dose 7 (Day 7) dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 7 infusion
Dose-Normalized Maximum Observed Concentration at Steady State (Cmax,ss/Dose) of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the dose-normalized Cmax,ss ((µg/mL)/mg) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group. This estimate assumes steady state has been achieved.
Time frame: =0.5 h prior to the start of Dose 7 (Day 7) dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 7 infusion
Average Concentration Over the Dose 7 Dosing Interval (Cavg) of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the average concentration over the Dose 7 dosing interval, Cavg (µg/mL) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration). Cavg is calculated as AUC(0-tau,ss)/tau. These estimates assume steady state has been achieved.
Time frame: =0.5 h prior to the start of Dose 7 (Day 7) dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 7 infusion
Predicted Concentration at the End of the Dosing Interval at Steady State (Ctau,ss) of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the predicted concentration at the end of the dosing interval at steady state, Ctau,ss (µg/mL), parameters estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration). These estimates assume steady state has been achieved.
Time frame: =0.5 h prior to the start of Dose 7 (Day 7) dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 7 infusion
Time of Maximum Concentration at Steady State (Tmax,ss) for Dose 7 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Median and minimum/maximum of the Tmax,ss (h) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group. The estimate for Tmax,ss assumes steady state has been achieved.
Time frame: =0.5 h prior to the start of Dose 7 (Day 7) dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 7 infusion
Time of Minimum Concentration (Tmin) for Dose 7 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Median and minimum/maximum of the Tmin (h) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group.
Time frame: =0.5 h prior to the start of Dose 7 (Day 7) dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 7 infusion
Area Under the Concentration-Time Curve From Dose 7 Dosing Extrapolated to 24 Hours After Dosing at Steady State (AUC(0-24),ss) of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the area under the concentration-time curve from dosing (time 0 h) extrapolated to 24 h after dosing at steady state, AUC(0-24),ss (µg\*h/mL), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration). This estimate assumes steady state has been achieved.
Time frame: =0.5 h prior to the start of Dose 7 (Day 7) dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 7 infusion
Area Under the Concentration-Time Curve From Dose 7 Dosing to the End of the Dosing Interval at Steady State (AUC(0-tau),ss) of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the area under the concentration-time curve from dosing (time 0 h) to the end of the dosing interval (24 h post-infusion) at steady state, AUC(0-tau),ss (µg\*h/mL), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration). This estimate assumes steady state has been achieved.
Time frame: =0.5 h prior to the start of Dose 7 (Day 7) dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 7 infusion
Dose-Normalized Area Under the Concentration-Time Curve From Dose 7 Dosing to the End of the Dosing Interval at Steady State (AUC(0-tau),ss/Dose) of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the dose-normalized total area under the concentration-time curve from dosing (time 0 h) to the end of the dosing interval (24 h post-infusion) at steady state, AUC(0-tau),ss/Dose ((µg\*h/mL)/mg), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration). This estimate assumes steady state has been achieved.
Time frame: =0.5 h prior to the start of Dose 7 (Day 7) dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 7 infusion
Terminal Elimination Half-Life (t1/2) for Dose 7 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the terminal elimination half-life, t1/2 (h), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
Time frame: =0.5 h prior to the start of Dose 7 (Day 7) dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 7 infusion
Total Clearance (CLT) for Dose 7 of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the total clearance, CLT (L/h), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
Time frame: =0.5 h prior to the start of Dose 7 (Day 7) dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 7 infusion
Apparent Volume of Distribution at Steady State (Vd,ss) of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the apparent volume of distribution at steady state, Vd,ss (L), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration). This estimate assumes steady state has been achieved.
Time frame: =0.5 h prior to the start of Dose 7 (Day 7) dosing and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 7 infusion
Linearity Index of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the linearity index (ratio) for the total ERT, free ERT, total ZID, and free ZID plasma concentration-time data by dose group. The linearity index is a measure of how linear the relationship is between increase in administered dose and increase in exposure. The linearity index is estimated as AUC(0-tau),ss (Dose 7)/AUC(0-inf) (Dose 1), where the areas under the concentration-time curves from Dose 7 to the end of the dosing interval at steady state and from Dose 1 taken to the limit as the end time becomes arbitrarily large, AUC(0-tau),ss and AUC(0-inf) respectively, are calculated using Phoenix WinNonlin Non-compartmental Analysis with Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration). The AUC(0-tau),ss estimate assumes steady state was reached.
Time frame: =0.5 h prior to the start of and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) and Dose 7 (Day 7) infusions
The Accumulation Ratio of the Area Under the Concentration-Time Curve (RAUC) of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the accumulation ratio of the AUC, RAUC (ratio), parameter for the total ERT, free ERT, total ZID, and free ZID plasma concentration-time data by dose group. RAUC is estimated as AUC(0-tau),ss (Dose 7)/AUC(0-24) (Dose 1), where the areas under the concentration-time curves from Dose 7 to the end of the dosing interval at steady state and from Dose 1 extrapolated to 24 h after Dose 1, AUC(0-tau),ss and AUC(0-24) respectively, are calculated using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration). The AUC(0-tau),ss estimate assumes steady state was reached.
Time frame: =0.5 h prior to the start of and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) and Dose 7 (Day 7) infusions
The Accumulation Ratio of the Maximum Observed Concentration (RCmax) of Total ERT, Free ERT, Total ZID, and Free ZID in Plasma
Geometric mean (GM), and coefficient of variation percentage (CV%) of the accumulation ratio of the Cmax, RCmax (ratio), parameter for the total ERT, free ERT, total ZID, and free ZID plasma concentration-time data by dose group. RCmax is estimated as Cmax (Dose 7)/Cmax (Dose 1), where the Cmax parameters are estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h periods following Dose 1 and Dose 7, respectively.
Time frame: =0.5 h prior to the start of and 0.25 h (WCK 6777 2g group only), 0.5 h (WCK 6777 2g, ERT 2g, ZID 2g, and WCK 6777 4g groups only), 1 h, 2 h, 3 h, 4 h, 8 h, 12 h, 18 h, and 24 h post-start of Dose 1 (Day 1) and Dose 7 (Day 7) infusions
Amounts of Unchanged ERT and Unchanged ZID Excreted in Urine (Ae,Urine) During Each Nominal Time Collection Interval Following Dose 1
Mean and minimum/maximum of the amount of unchanged ERT and the amount of unchanged ZID excreted in urine, Ae,urine (mg), during 0-4 h, 4-8 h, 8-12 h, and 12-24 h following Dose 1 by dose group. Ae,urine parameters are calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
Time frame: 0-4 h, 4-8 h, 8-12 h, and 12-24 h post-start of Dose 1 (Day 1) infusion
Cumulative Amounts of Unchanged ERT and Unchanged ZID Excreted in Urine From Zero (Predose) to 24 h Following Dose 1 (Ae,Urine(0-24))
Mean and minimum/maximum of the cumulative amount of unchanged ERT and the cumulative amount of unchanged ZID excreted in urine from zero (predose) to 24 h following Dose 1, Ae,urine(0-24) (mg), by dose group. This parameter is calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
Time frame: 0-1 h pre-start of Dose 1 (Day 1) infusion and 0-4 h, 4-8 h, 8-12 h, and 12-24 h post-start of Dose 1 infusion
Fractions (%) of ERT and ZID Excreted Unchanged in Urine (fe,Urine) During Each Nominal Time Collection Interval Following Dose 1
Mean and minimum/maximum of the fraction of ERT and the fraction of ZID excreted unchanged in urine, fe,urine (%), during 0-4 h, 4-8 h, 8-12 h, and 12-24 h following Dose 1 by dose group. These fe,urine parameters are calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
Time frame: 0-4 h, 4-8 h, 8-12 h, and 12-24 h post-start of Dose 1 (Day 1) infusion
Fractions (%) of ERT and ZID Excreted Unchanged in Urine From Zero (Predose) to 24 h Following Dose 1 (fe,Urine(0-24))
Mean and minimum/maximum of the fraction of ERT and the fraction of ZID excreted unchanged in urine from zero (predose) to 24 h following Dose 1, fe,urine(0-24) (%), by dose group. This parameter is calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
Time frame: 0-1 h pre-start of Dose 1 (Day 1) infusion and 0-4 h, 4-8 h, 8-12 h, and 12-24 h post-start of Dose 1 infusion
Renal Clearance of ERT and ZID From Dosing Until the Last Collected Concentration for Dose 1 (CLR(0-24))
Geometric mean (GM), and coefficient of variation percentage (CV%) of renal clearance of ERT and ZID from dosing until the last collected concentration for Dose 1 (24 h postdose), CLR(0-24) (mL/h ), by dose group. This parameter is calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
Time frame: 0-1 h pre-start of Dose 1 (Day 1) infusion and 0-4 h, 4-8 h, 8-12 h, and 12-24 h post-start of Dose 1 infusion
Amounts of Unchanged ERT and Unchanged ZID Excreted in Urine (Ae,Urine) During Each Nominal Time Collection Interval Following Dose 7
Mean and minimum/maximum of the amount of unchanged ERT and the amount of unchanged ZID excreted in urine, Ae,urine (mg), during 0-4 h, 4-8 h, 8-12 h, and 12-24 h following Dose 7 by dose group. Ae,urine parameters are calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
Time frame: 0-4 h, 4-8 h, 8-12 h, and 12-24 h post-start of Dose 7 (Day 7) infusion
Cumulative Amounts of Unchanged ERT and Unchanged ZID Excreted in Urine From Zero (Predose) to 24 h Following Dose 7 (Ae,Urine(0-24),SS)
Mean and minimum/maximum of the cumulative amount of unchanged ERT and the cumulative amount of unchanged ZID excreted in urine from zero (predose) to 24 h following Dose 7, Ae,urine(0-24) (mg), by dose group. This parameter is calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
Time frame: 0-1 h pre-start of Dose 7 (Day 7) infusion and 0-4 h, 4-8 h, 8-12 h, and 12-24 h post-start of Dose 7 infusion
Fractions (%) of ERT and ZID Excreted Unchanged in Urine (fe,Urine) During Each Nominal Time Collection Interval Following Dose 7
Mean and minimum/maximum of the fraction of ERT and the fraction of ZID excreted unchanged in urine, fe,urine (%), during 0-4 h, 4-8 h, 8-12 h, and 12-24 h following Dose 7 by dose group. These fe,urine parameters are calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
Time frame: 0-4 h, 4-8 h, 8-12 h, and 12-24 h post-start of Dose 7 (Day 7) infusion
Fractions (%) of ERT and ZID Excreted Unchanged in Urine From Zero (Predose) to 24 h Following Dose 7 (fe,Urine(0-24),SS)
Mean and minimum/maximum of the fraction of ERT and the fraction of ZID excreted unchanged in urine from zero (predose) to 24 h following Dose 7, fe,urine(0-24) (%), by dose group. This parameter is calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
Time frame: 0-1 h pre-start of Dose 7 (Day 7) infusion and 0-4 h, 4-8 h, 8-12 h, and 12-24 h post-start of Dose 7 infusion
Renal Clearance of ERT and ZID From Dosing Until the Last Collected Concentration for Dose 7 (CLR(0-24),SS)
Geometric mean (GM), and coefficient of variation percentage (CV%) of renal clearance of ERT and ZID from dosing until the last collected concentration for Dose 7 (24 h postdose), CLR(0-24) (mL/h), by dose group. This parameter is calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
Time frame: 0-1 h pre-start of Dose 7 (Day 7) infusion and 0-4 h, 4-8 h, 8-12 h, and 12-24 h post-start of Dose 7 infusion
Participants were recruited between 19APR2023 and 24OCT2023 by the clinical trials unit (CTU) utilizing the CTU subject database and IRB-approved advertisements and social media.
| Milestone | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g | Placebo |
|---|---|---|---|---|---|---|---|---|
| Started | 6 | 6 | 6 | 6 | 7 | 7 | 6 | 10 |
| Completed | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 10 |
| Not completed | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
| Withdrew: Enrolled but treatment not administered | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
Adverse events (AEs) are defined as any untoward medical occurrence in a participant or clinical investigation participant who was administered a pharmaceutical product, regardless of its causal relationship to the product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of the product, and are described as treatment-emergent AEs (TEAEs). Number of participants with a TEAE are summarized by dose group and by MedDRA System Organ Class (SOC).
| Participants | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g | Placebo |
|---|---|---|---|---|---|---|---|---|
| Blood and lymphatic system disorders | 0 | 1 | 1 | 0 | 0 | 0 | 1 | 1 |
| Gastrointestinal disorders | 2 | 2 | 0 | 1 | 1 | 0 | 1 | 1 |
| General disorders and administration site conditions | 3 | 5 | 5 | 4 | 4 | 2 | 3 | 6 |
| Infections and infestations | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Injury, poisoning and procedural complications | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Investigations | 1 | 0 | 1 | 1 | 1 | 0 | 1 | 3 |
| Musculoskeletal and connective tissue disorders | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Nervous system disorders | 1 | 1 | 1 | 0 | 1 | 0 | 0 | 2 |
| Renal and urinary disorders | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Respiratory, thoracic and mediastinal disorders | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Skin and subcutaneous tissue disorders | 1 | 0 | 3 | 0 | 0 | 0 | 0 | 1 |
Adverse events (AEs) are defined as any untoward medical occurrence in a participant or clinical investigation participant who was administered a pharmaceutical product, regardless of its causal relationship to the product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of the product, and are described as treatment-emergent AEs (TEAEs). Number of TEAEs reported are summarized by dose group and MedDRA System Organ Class (SOC)..
| events | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g | Placebo |
|---|---|---|---|---|---|---|---|---|
| Blood and lymphatic system disorders | 0 | 1 | 1 | 0 | 0 | 0 | 1 | 1 |
| Gastrointestinal disorders | 3 | 2 | 0 | 1 | 1 | 0 | 1 | 1 |
| General disorders and administration site conditions | 6 | 11 | 8 | 6 | 6 | 3 | 6 | 14 |
| Infections and infestations | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Injury, poisoning and procedural complications | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Investigations | 1 | 0 | 1 | 1 | 2 | 0 | 1 | 3 |
| Musculoskeletal and connective tissue disorders | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Nervous system disorders | 1 | 1 | 1 | 0 | 1 | 0 | 0 | 2 |
| Renal and urinary disorders | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Respiratory, thoracic and mediastinal disorders | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Skin and subcutaneous tissue disorders | 1 | 0 | 3 | 0 | 0 | 0 | 0 | 1 |
Adverse events (AEs) are defined as any untoward medical occurrence in a participant or clinical investigation participant who was administered a pharmaceutical product, regardless of its causal relationship to the product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of the product, and are described as treatment-emergent AEs (TEAEs). TEAEs are assessed by the investigator to determine relationship to the study drug. Number of participants with a related TEAE are summarized by dose group and by MedDRA System Organ Class (SOC).
| Participants | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g | Placebo |
|---|---|---|---|---|---|---|---|---|
| Blood and lymphatic system disorders | 0 | 1 | 1 | 0 | 0 | 0 | 1 | 1 |
| Gastrointestinal disorders | 2 | 2 | 0 | 1 | 1 | 0 | 1 | 1 |
| General disorders and administration site conditions | 3 | 5 | 4 | 3 | 2 | 2 | 3 | 4 |
| Infections and infestations | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Injury, poisoning and procedural complications | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Investigations | 1 | 0 | 0 | 1 | 1 | 0 | 1 | 2 |
| Musculoskeletal and connective tissue disorders | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Nervous system disorders | 1 | 1 | 1 | 0 | 1 | 0 | 0 | 2 |
| Renal and urinary disorders | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Respiratory, thoracic and mediastinal disorders | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Skin and subcutaneous tissue disorders | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Serious AEs (SAEs) meet one or more of the following criteria: death, life-threatening AEs, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, substantial disruption of the ability to conduct normal life function, congenital anomaly/birth defect, or important medical events that may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. SAEs are listed.
| events | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g | Placebo |
|---|---|---|---|---|---|---|---|---|
| Number of Serious Adverse Events Reported | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Parameters and thresholds include alanine aminotransferase =33 (female (F) 19Y), =30 (F \>19) or =47 U/L (male (M) =19Y); albumin =3.5 g/dL; alkaline phosphatase =129 (F 19Y), =126 (F =49Y), =170 (M 19Y) or =131 U/L (M =49Y); aspartate aminotransferase =33 (19Y) or =41 U/L (20-49Y); bilirubin =1.2 (19Y) or =1.3 mg/dL (\>19Y); calcium =8.8 (4-19Y), =8.5 (20-49Y), =10.5 (4-19Y), =10.3 (F 20-49Y) or =10.4 mg/dL (M 20-49Y); carbon dioxide =19 or =33 mmol/L; creatinine =0.97 (F 18-29Y), =0.98 (F 30-39Y), =1.00 (F 40-49Y), =1.25 (M 18-29Y), =1.27 (M 30-39Y) or =1.30 mg/dL (M 40-49Y); direct bilirubin =0.3 mg/dL; glucose =64 or =100 mg/dL; potassium =3.7 (19Y), =3.4 (\>19Y), = 5.2 (19Y) or = 5.4 mmol/L (\>19Y); protein =6.2 (19Y) or =6.0 g/dL (\>19Y); sodium =134 or =147 mmol/L; and urea nitrogen =21 (19Y) or =26 mg/dL (\>19Y). All abnormal toxicity results are included, but Grade 1 values at screening/baseline allowed for enrollment were only considered TEAEs if they increased in severity.
| Participants | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g | Placebo |
|---|---|---|---|---|---|---|---|---|
| Alanine aminotransferase increase | 0 | 2 | 0 | 2 | 2 | 0 | 1 | 1 |
| Albumin decrease | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Alkaline phosphatase increase | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Aspartate aminotransferase increase | 0 | 1 | 0 | 1 | 1 | 0 | 0 | 0 |
| Bilirubin increase | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Calcium decrease | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 |
| Calcium increase | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Carbon dioxide decrease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Carbon dioxide increase | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
| Creatinine increase | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 0 |
| Direct bilirubin increase | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Glucose decrease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Glucose increase | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 1 |
| Potassium decrease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Potassium increase | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Protein decrease | 0 | 0 | 1 | 2 | 0 | 0 | 0 | 0 |
| Sodium decrease | 1 | 0 | 0 | 1 | 1 | 1 | 0 | 1 |
| Sodium increase | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Urea nitrogen increase | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Parameters and thresholds include basophils =201 x106/L (\>6Y); eosinophils =501 x106/L (\>6Y); hemoglobin =11.4 (female (F) 18Y), =11.6 (F \>18Y), =11.9 (male (M) 18Y) or =13.1 g/dL (M \>18Y); leukocytes =4.4 (18Y), =3.7 (\>18Y), =13.1 (18Y) or =10.9 x109/L (\>18Y); lymphocytes =1199 (18Y) or =849 x106/L (\>18Y); monocytes =901 (18Y) or =951 x106/L (\>18Y); neutrophils =1799 (18Y) or =1499 x106/L (\>18Y); and platelets \<140 x109/L. All abnormal toxicity results are included, but Grade 1 values at screening/baseline allowed for enrollment were only considered TEAEs if they increased in severity.
| Participants | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g | Placebo |
|---|---|---|---|---|---|---|---|---|
| Basophils increase | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Eosinophils increase | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Hemoglobin decrease | 3 | 2 | 2 | 2 | 2 | 2 | 2 | 5 |
| Leukocytes decrease | 3 | 0 | 0 | 2 | 2 | 0 | 3 | 2 |
| Leukocytes increase | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Lymphocytes decrease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Monocytes increase | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Neutrophils decrease | 1 | 0 | 0 | 2 | 1 | 0 | 2 | 2 |
| Platelets decrease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Parameters and thresholds include activated partial thromboplastin time \>32 s, prothrombin intl. normalized ratio \>1.1 (ratio), and prothrombin time \>11.5 s. All abnormal toxicity results are included, but Grade 1 values at screening/baseline allowed for enrollment were only considered TEAEs if they increased in severity.
| Participants | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g | Placebo |
|---|---|---|---|---|---|---|---|---|
| Activated partial thromboplastin time increase | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Prothrombin intl. normalized ratio (INR) increase | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Prothrombin time increase | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 1 |
Parameters and thresholds include dipstick measurements of glucose =1+, leukocyte esterase =1+, occult blood =1+, protein =1+ and urinalysis with microscopy results of at least a few bacteria, red blood cells (RBC) =3 per high-powered field (HPF), and white blood cells (WBC) =6 per HPF. If dipstick results were abnormal, urinalysis with microscopy was performed. All abnormal toxicity results are included, but Grade 1 values at screening/baseline allowed for enrollment were only considered TEAEs if they increased in severity.
| Participants | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g | Placebo |
|---|---|---|---|---|---|---|---|---|
| Glucose increase | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Leukocyte esterase increase | 1 | 1 | 1 | 1 | 0 | 1 | 0 | 2 |
| Occult blood increase | 1 | 2 | 0 | 0 | 0 | 0 | 0 | 1 |
| Protein increase | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| RBC increase | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| WBC increase | 1 | 2 | 0 | 0 | 0 | 1 | 0 | 1 |
| Bacteria increase | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 3 |
The only ECG parameters graded were PR interval with a threshold of =211 msec and QTcF interval with a threshold of =471 msec (female) or =451 msec (male) or an increase of =30 msec above baseline. ECG values after dosing were considered as TEAEs if they met toxicity grading criteria.
| Participants | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g | Placebo |
|---|---|---|---|---|---|---|---|---|
| PR interval | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| QTcF interval | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 |
VS parameters and thresholds include diastolic blood pressure =90 mmHg, oral temperature =37.3 °C, pulse =49 or =101 beats/min, respiratory rate =21 breaths/min, and systolic blood pressure =88 or =131 mmHg. VS could be repeated up to twice more at rest and within at least 5 minutes of each other. The following rules were used to determine which vital sign measurement to use for analysis if repeat measurements occurred: 1. If the first replicate was normal, it was used. 2. If the first and second replicates were both abnormal, the replicate with the higher severity was used. 3. If the first replicate was abnormal, the second replicate was normal, and the third replicate was not performed, the first replicate was used. 4. If the first replicate was abnormal and the second and third replicates were normal, the second replicate was used. 5. If the first and third replicates were abnormal and the second replicate was normal, the abnormal replicate with the higher severity was used.
| Participants | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g | Placebo |
|---|---|---|---|---|---|---|---|---|
| Diastolic blood pressure increase | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Oral temperature increase | 1 | 0 | 0 | 1 | 0 | 0 | 1 | 2 |
| Pulse decrease | 1 | 0 | 0 | 0 | 1 | 0 | 2 | 0 |
| Pulse increase | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Respiratory rate increase | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Systolic blood pressure decrease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Systolic blood pressure increase | 2 | 0 | 1 | 0 | 0 | 1 | 0 | 1 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the Cmax (µg/mL) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group.
| µg/mL | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 196.66 ± 14 | 303.43 ± 9 | — | 354.41 ± 8 | 378.71 ± 10 | — | 391.87 ± 13 |
| Free ERT | 16.60 ± 17 | 34.00 ± 17 | — | 42.10 ± 22 | 58.45 ± 17 | — | 59.42 ± 19 |
| Total ZID | 69.67 ± 15 | — | 120.41 ± 22 | 133.51 ± 16 | — | 111.71 ± 10 | 128.42 ± 11 |
| Free ZID | 64.35 ± 20 | — | 105.42 ± 16 | 98.41 ± 55 | — | 108.79 ± 11 | 124.99 ± 10 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the Cmin (µg/mL) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group.
| µg/mL | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 2.15 ± 50 | 2.61 ± 107 | — | 3.10 ± 60 | 7.32 ± 14 | — | 5.91 ± 33 |
| Free ERT | 0.10 ± 40 | 0.16 ± 42 | — | 0.14 ± 67 | 0.36 ± 24 | — | 0.28 ± 35 |
| Total ZID | 0.09 ± 37 | — | 0.11 ± 72 | 0.10 ± 44 | — | 0.13 ± 28 | 0.15 ± 30 |
| Free ZID | 0.09 ± 22 | — | 0.07 ± 36 | 0.10 ± 39 | — | 0.14 ± 26 | 0.14 ± 34 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the Ctau (µg/mL) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group. Ctau is estimated using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
| µg/mL | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 2.02 ± 50 | 2.29 ± 112 | — | 2.83 ± 61 | 6.83 ± 16 | — | 5.44 ± 34 |
| Free ERT | 0.08 ± 39 | 0.10 ± 102 | — | 0.13 ± 67 | 0.31 ± 23 | — | 0.27 ± 38 |
| Total ZID | 0.02 ± 101 | — | 0.06 ± 69 | 0.05 ± 87 | — | 0.11 ± 33 | 0.13 ± 31 |
| Free ZID | 0.04 ± 102 | — | 0.06 ± 49 | 0.05 ± 96 | — | 0.11 ± 34 | 0.12 ± 34 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the dose-normalized Cmax ((µg/mL)/mg) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group
| (µg/mL)/mg | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 0.20 ± 14 | 0.15 ± 9 | — | 0.18 ± 8 | 0.13 ± 10 | — | 0.13 ± 14 |
| Free ERT | 0.02 ± 17 | 0.02 ± 17 | — | 0.02 ± 22 | 0.02 ± 17 | — | 0.02 ± 19 |
| Total ZID | 0.07 ± 15 | — | 0.06 ± 22 | 0.07 ± 16 | — | 0.04 ± 10 | 0.04 ± 11 |
| Free ZID | 0.06 ± 20 | — | 0.05 ± 16 | 0.05 ± 55 | — | 0.04 ± 11 | 0.04 ± 10 |
Median and minimum/maximum of the Tmax (h) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group.
| hours | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 0.50 (0.50 to 0.50) | 1.00 (1.00 to 1.07) | — | 1.00 (1.00 to 1.00) | 2.02 (2.00 to 2.03) | — | 2.03 (2.02 to 2.03) |
| Free ERT | 0.50 (0.50 to 0.50) | 1.00 (1.00 to 1.07) | — | 1.00 (1.00 to 1.00) | 2.02 (2.02 to 2.03) | — | 2.03 (2.02 to 2.03) |
| Total ZID | 0.50 (0.50 to 0.50) | — | 1.03 (1.02 to 1.03) | 1.00 (1.00 to 1.00) | — | 2.02 (1.03 to 2.02) | 2.03 (2.02 to 2.03) |
| Free ZID | 0.50 (0.50 to 0.50) | — | 1.03 (1.02 to 1.03) | 1.00 (1.00 to 2.00) | — | 2.02 (1.03 to 2.02) | 2.03 (2.02 to 2.03) |
Median and minimum/maximum of the Tmin (h) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group.
| hours | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 23.60 (23.60 to 23.70) | 23.65 (23.60 to 23.70) | — | 23.60 (23.60 to 23.60) | 23.60 (23.40 to 23.60) | — | 23.60 (23.60 to 23.70) |
| Free ERT | 23.60 (18.00 to 23.60) | 23.60 (18.00 to 23.70) | — | 23.60 (23.60 to 23.60) | 23.60 (23.40 to 23.60) | — | 23.60 (23.60 to 23.70) |
| Total ZID | 18.00 (18.00 to 23.60) | — | 23.60 (18.00 to 23.70) | 23.60 (18.00 to 23.60) | — | 23.60 (23.60 to 23.60) | 23.60 (23.60 to 23.70) |
| Free ZID | 23.60 (18.00 to 23.70) | — | 23.60 (23.60 to 23.70) | 23.60 (18.00 to 23.60) | — | 23.60 (23.60 to 23.60) | 23.60 (23.60 to 23.70) |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the total area under the concentration-time curve from dosing (time 0 h) extrapolated to the time the concentration is predicted to reach the lower limit of quantification (LLOQ), AUC(0-t) (µg\*h/mL), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
| µg*h/mL | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 723.48 ± 9 | 1241.47 ± 18 | — | 1377.99 ± 14 | 2148.23 ± 11 | — | 2024.46 ± 10 |
| Free ERT | 39.92 ± 7 | 83.95 ± 19 | — | 102.81 ± 24 | 187.42 ± 15 | — | 190.43 ± 14 |
| Total ZID | 140.00 ± 8 | — | 302.40 ± 18 | 320.50 ± 20 | — | 379.92 ± 9 | 442.32 ± 14 |
| Free ZID | 125.17 ± 8 | — | 257.74 ± 15 | 247.40 ± 42 | — | 379.75 ± 11 | 427.31 ± 16 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the total area under the concentration-time curve from dosing (time 0 h) to the time of last measured concentration, AUC(0-last) (µg\*h/mL),parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group.
| µg*h/mL | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 728.18 ± 9 | 1247.86 ± 18 | — | 1384.69 ± 14 | 2153.20 ± 11 | — | 2027.57 ± 10 |
| Free ERT | 41.04 ± 7 | 85.03 ± 19 | — | 103.94 ± 23 | 188.66 ± 15 | — | 191.81 ± 14 |
| Total ZID | 141.17 ± 8 | — | 303.42 ± 18 | 321.35 ± 20 | — | 381.44 ± 9 | 443.70 ± 14 |
| Free ZID | 126.34 ± 8 | — | 259.11 ± 15 | 248.60 ± 42 | — | 380.91 ± 11 | 428.67 ± 16 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the total area under the concentration-time curve from dosing (time 0 h) taken to the limit as the end time becomes arbitrarily large, AUC(0-inf) (µg\*h/mL), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
| µg*h/mL | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 742.95 ± 10 | 1265.39 ± 19 | — | 1404.86 ± 15 | 2199.93 ± 11 | — | 2065.37 ± 11 |
| Free ERT | 41.65 ± 7 | 85.93 ± 19 | — | 104.94 ± 24 | 190.81 ± 15 | — | 193.61 ± 14 |
| Total ZID | 141.33 ± 8 | — | 303.92 ± 18 | 322.04 ± 20 | — | 381.76 ± 9 | 444.34 ± 14 |
| Free ZID | 126.50 ± 8 | — | 259.27 ± 15 | 249.11 ± 41 | — | 381.44 ± 11 | 429.33 ± 16 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the total area under the concentration-time curve from dosing (time 0 h) extrapolated to 24 h after dosing, AUC(0-24) (µg\*h/mL), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
| µg*h/mL | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 728.97 ± 9 | 1249.60 ± 18 | — | 1386.28 ± 14 | 2156.38 ± 11 | — | 2029.12 ± 10 |
| Free ERT | 41.19 ± 7 | 85.25 ± 19 | — | 103.96 ± 23 | 188.86 ± 15 | — | 192.13 ± 14 |
| Total ZID | 141.17 ± 8 | — | 303.60 ± 18 | 321.76 ± 20 | — | 381.59 ± 9 | 443.70 ± 14 |
| Free ZID | 126.34 ± 8 | — | 259.11 ± 15 | 248.60 ± 42 | — | 380.91 ± 11 | 428.67 ± 16 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the total area under the concentration-time curve from dosing (time 0 h) to the end of the dosing interval (24 h post-infusion), AUC(0-tau) (µg\*h/mL), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration
| µg*h/mL | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 728.97 ± 9 | 1249.60 ± 18 | — | 1386.28 ± 14 | 2156.38 ± 11 | — | 2029.12 ± 10 |
| Free ERT | 41.19 ± 7 | 85.25 ± 19 | — | 103.96 ± 23 | 188.86 ± 15 | — | 192.13 ± 14 |
| Total ZID | 141.17 ± 8 | — | 303.60 ± 18 | 321.76 ± 20 | — | 381.59 ± 9 | 443.70 ± 14 |
| Free ZID | 126.34 ± 8 | — | 259.11 ± 15 | 248.60 ± 42 | — | 380.91 ± 11 | 428.67 ± 16 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the dose-normalized total area under the concentration-time curve from dosing (time 0 h) to the end of the dosing interval (24 h post-infusion), AUC(0-tau)/Dose ((µg\*h/mL)/mg), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
| (µg*h/mL)/mg | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 0.73 ± 9 | 0.62 ± 18 | — | 0.69 ± 15 | 0.72 ± 11 | — | 0.68 ± 10 |
| Free ERT | 0.04 ± 7 | 0.04 ± 19 | — | 0.05 ± 24 | 0.06 ± 15 | — | 0.06 ± 14 |
| Total ZID | 0.14 ± 8 | — | 0.15 ± 18 | 0.16 ± 20 | — | 0.13 ± 9 | 0.15 ± 14 |
| Free ZID | 0.13 ± 8 | — | 0.13 ± 15 | 0.12 ± 41 | — | 0.13 ± 11 | 0.14 ± 16 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the terminal elimination half-life, t1/2 (h), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
| hours | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 4.34 ± 12 | 3.76 ± 22 | — | 3.92 ± 14 | 4.20 ± 4 | — | 4.20 ± 10 |
| Free ERT | 4.09 ± 11 | 3.83 ± 21 | — | 3.86 ± 15 | 3.96 ± 12 | — | 3.87 ± 10 |
| Total ZID | 2.35 ± 15 | — | 2.60 ± 14 | 2.57 ± 12 | — | 2.61 ± 9 | 2.71 ± 6 |
| Free ZID | 2.75 ± 18 | — | 2.81 ± 14 | 2.63 ± 15 | — | 2.69 ± 9 | 2.71 ± 5 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the total clearance, CLT (L/h), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
| L/h | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 1.34 ± 10 | 1.58 ± 19 | — | 1.42 ± 15 | 1.37 ± 11 | — | 1.45 ± 11 |
| Free ERT | 23.99 ± 7 | 23.28 ± 19 | — | 19.06 ± 24 | 15.70 ± 15 | — | 15.50 ± 14 |
| Total ZID | 7.07 ± 8 | — | 6.58 ± 18 | 6.21 ± 20 | — | 7.86 ± 9 | 6.75 ± 14 |
| Free ZID | 7.91 ± 8 | — | 7.71 ± 15 | 8.03 ± 41 | — | 7.86 ± 11 | 6.99 ± 16 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the first-order terminal phase elimination rate constant, Ke (1/h), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
| 1/h | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 0.16 ± 12 | 0.18 ± 22 | — | 0.18 ± 14 | 0.17 ± 4 | — | 0.17 ± 10 |
| Free ERT | 0.17 ± 11 | 0.18 ± 21 | — | 0.18 ± 15 | 0.18 ± 12 | — | 0.18 ± 10 |
| Total ZID | 0.30 ± 15 | — | 0.27 ± 14 | 0.27 ± 12 | — | 0.27 ± 9 | 0.26 ± 6 |
| Free ZID | 0.25 ± 18 | — | 0.25 ± 14 | 0.26 ± 14 | — | 0.26 ± 9 | 0.26 ± 5 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the apparent volume of distribution, Vd (L), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 1 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
| liters | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 8.43 ± 7 | 8.57 ± 9 | — | 8.04 ± 12 | 8.28 ± 10 | — | 8.81 ± 13 |
| Free ERT | 141.43 ± 11 | 128.25 ± 12 | — | 106.20 ± 23 | 89.98 ± 20 | — | 86.55 ± 16 |
| Total ZID | 23.97 ± 14 | — | 24.67 ± 28 | 23.05 ± 22 | — | 29.56 ± 10 | 26.43 ± 16 |
| Free ZID | 31.37 ± 12 | — | 31.18 ± 23 | 30.42 ± 40 | — | 30.52 ± 9 | 27.28 ± 17 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the Cmax,ss (µg/mL) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group. These estimates assume steady state has been achieved.
| µg/mL | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 181.90 ± 11 | 341.92 ± 10 | — | 344.89 ± 10 | 387.57 ± 9 | — | 343.24 ± 13 |
| Free ERT | 15.41 ± 24 | 38.18 ± 13 | — | 36.09 ± 23 | 57.65 ± 28 | — | 50.36 ± 28 |
| Total ZID | 63.87 ± 17 | — | 115.71 ± 16 | 130.69 ± 18 | — | 109.41 ± 7 | 113.79 ± 16 |
| Free ZID | 57.89 ± 23 | — | 103.12 ± 18 | 83.36 ± 57 | — | 111.59 ± 7 | 111.81 ± 16 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the Cmin,ss (µg/mL) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group. These estimates assume steady state has been achieved.
| µg/mL | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 1.75 ± 30 | 1.81 ± 114 | — | 1.74 ± 75 | 4.93 ± 2 | — | 3.49 ± 65 |
| Free ERT | 0.10 ± 28 | 0.12 ± 35 | — | 0.12 ± 60 | 0.23 ± 31 | — | 0.15 ± 59 |
| Total ZID | 0.13 ± 49 | — | 0.12 ± 68 | 0.10 ± 46 | — | 0.13 ± 27 | 0.12 ± 36 |
| Free ZID | 0.12 ± 66 | — | 0.10 ± 38 | 0.17 ± 864 | — | 0.14 ± 23 | 0.11 ± 34 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the dose-normalized Cmax,ss ((µg/mL)/mg) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group. This estimate assumes steady state has been achieved.
| (µg/mL)/mg | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 0.18 ± 11 | 0.17 ± 10 | — | 0.17 ± 10 | 0.13 ± 9 | — | 0.11 ± 13 |
| Free ERT | 0.02 ± 24 | 0.02 ± 13 | — | 0.02 ± 23 | 0.02 ± 28 | — | 0.02 ± 28 |
| Total ZID | 0.06 ± 17 | — | 0.06 ± 16 | 0.07 ± 18 | — | 0.04 ± 7 | 0.04 ± 16 |
| Free ZID | 0.06 ± 23 | — | 0.05 ± 18 | 0.04 ± 56 | — | 0.04 ± 7 | 0.04 ± 15 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the average concentration over the Dose 7 dosing interval, Cavg (µg/mL) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration). Cavg is calculated as AUC(0-tau,ss)/tau. These estimates assume steady state has been achieved.
| µg/mL | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 29.99 ± 9 | 51.20 ± 13 | — | 51.40 ± 16 | 80.91 ± 6 | — | 71.98 ± 14 |
| Free ERT | 1.64 ± 6 | 3.51 ± 18 | — | 3.77 ± 16 | 7.01 ± 23 | — | 6.29 ± 19 |
| Total ZID | 5.56 ± 8 | — | 11.94 ± 20 | 12.83 ± 19 | — | 16.05 ± 7 | 16.52 ± 14 |
| Free ZID | 5.03 ± 8 | — | 10.48 ± 20 | 9.77 ± 30 | — | 16.32 ± 8 | 15.83 ± 14 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the predicted concentration at the end of the dosing interval at steady state, Ctau,ss (µg/mL), parameters estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration). These estimates assume steady state has been achieved.
| µg/mL | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 1.75 ± 30 | 1.85 ± 111 | — | 1.74 ± 75 | 4.93 ± 2 | — | 3.50 ± 64 |
| Free ERT | 0.06 ± 53 | 0.07 ± 128 | — | 0.07 ± 88 | 0.23 ± 31 | — | 0.15 ± 58 |
| Total ZID | 0.02 ± 68 | — | 0.06 ± 89 | 0.05 ± 176 | — | 0.13 ± 28 | 0.12 ± 35 |
| Free ZID | 0.06 ± 169 | — | 0.07 ± 90 | 0.11 ± 2318 | — | 0.14 ± 23 | 0.11 ± 34 |
Median and minimum/maximum of the Tmax,ss (h) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group. The estimate for Tmax,ss assumes steady state has been achieved.
| hours | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 0.52 (0.50 to 0.60) | 1.00 (1.00 to 1.00) | — | 1.02 (1.00 to 1.02) | 2.02 (2.02 to 2.02) | — | 2.07 (2.02 to 2.23) |
| Free ERT | 0.52 (0.25 to 0.60) | 1.00 (1.00 to 1.00) | — | 1.02 (0.50 to 1.02) | 2.02 (2.02 to 2.02) | — | 2.07 (2.02 to 2.23) |
| Total ZID | 0.52 (0.25 to 0.60) | — | 1.00 (1.00 to 1.00) | 1.02 (1.00 to 1.02) | — | 2.02 (2.02 to 2.07) | 2.07 (2.02 to 2.23) |
| Free ZID | 0.52 (0.25 to 0.60) | — | 1.00 (1.00 to 1.00) | 1.02 (1.00 to 2.00) | — | 2.02 (2.02 to 2.07) | 2.07 (2.02 to 2.23) |
Median and minimum/maximum of the Tmin (h) parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group.
| hours | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 24.00 (24.00 to 24.00) | 24.05 (24.00 to 24.30) | — | 24.00 (24.00 to 24.00) | 24.00 (24.00 to 24.00) | — | 24.00 (24.00 to 24.10) |
| Free ERT | 24.00 (18.00 to 24.00) | 24.00 (18.00 to 24.10) | — | 24.00 (18.00 to 24.00) | 24.00 (24.00 to 24.00) | — | 24.00 (24.00 to 24.10) |
| Total ZID | 18.00 (18.00 to 24.00) | — | 24.00 (18.00 to 24.00) | 24.00 (18.00 to 24.00) | — | 24.00 (24.00 to 24.10) | 24.00 (24.00 to 24.10) |
| Free ZID | 24.00 (18.00 to 24.00) | — | 24.00 (18.10 to 24.00) | 24.00 (18.00 to 24.00) | — | 24.00 (24.00 to 24.10) | 24.00 (24.00 to 24.10) |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the area under the concentration-time curve from dosing (time 0 h) extrapolated to 24 h after dosing at steady state, AUC(0-24),ss (µg\*h/mL), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration). This estimate assumes steady state has been achieved.
| µg*h/mL | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 719.86 ± 9 | 1228.88 ± 14 | — | 1233.66 ± 16 | 1940.84 ± 6 | — | 1726.43 ± 14 |
| Free ERT | 39.48 ± 6 | 84.22 ± 18 | — | 90.51 ± 16 | 168.05 ± 23 | — | 150.93 ± 19 |
| Total ZID | 133.35 ± 8 | — | 286.34 ± 20 | 308.35 ± 19 | — | 384.53 ± 7 | 396.60 ± 14 |
| Free ZID | 120.70 ± 8 | — | 251.56 ± 20 | 234.14 ± 30 | — | 392.09 ± 8 | 380.11 ± 14 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the area under the concentration-time curve from dosing (time 0 h) to the end of the dosing interval (24 h post-infusion) at steady state, AUC(0-tau),ss (µg\*h/mL), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration). This estimate assumes steady state has been achieved.
| µg*h/mL | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 719.86 ± 9 | 1228.88 ± 14 | — | 1233.66 ± 16 | 1940.84 ± 6 | — | 1726.43 ± 14 |
| Free ERT | 39.48 ± 6 | 84.22 ± 18 | — | 90.51 ± 16 | 168.05 ± 23 | — | 150.93 ± 19 |
| Total ZID | 133.35 ± 8 | — | 286.34 ± 20 | 308.35 ± 19 | — | 384.53 ± 7 | 396.60 ± 14 |
| Free ZID | 120.70 ± 8 | — | 251.56 ± 20 | 234.14 ± 30 | — | 392.09 ± 8 | 380.11 ± 14 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the dose-normalized total area under the concentration-time curve from dosing (time 0 h) to the end of the dosing interval (24 h post-infusion) at steady state, AUC(0-tau),ss/Dose ((µg\*h/mL)/mg), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration). This estimate assumes steady state has been achieved.
| (µg*h/mL)/mg | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 0.72 ± 9 | 0.61 ± 13 | — | 0.62 ± 16 | 0.65 ± 6 | — | 0.58 ± 14 |
| Free ERT | 0.04 ± 6 | 0.04 ± 18 | — | 0.05 ± 16 | 0.06 ± 23 | — | 0.05 ± 19 |
| Total ZID | 0.13 ± 8 | — | 0.14 ± 20 | 0.15 ± 19 | — | 0.13 ± 7 | 0.13 ± 14 |
| Free ZID | 0.12 ± 8 | — | 0.13 ± 20 | 0.12 ± 30 | — | 0.13 ± 8 | 0.13 ± 14 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the terminal elimination half-life, t1/2 (h), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
| hours | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 3.91 ± 8 | 3.64 ± 19 | — | 3.67 ± 21 | 4.14 ± 4 | — | 3.86 ± 18 |
| Free ERT | 3.89 ± 19 | 3.45 ± 19 | — | 3.38 ± 19 | 3.77 ± 10 | — | 3.76 ± 17 |
| Total ZID | 2.32 ± 15 | — | 2.64 ± 12 | 2.47 ± 24 | — | 2.69 ± 3 | 2.65 ± 10 |
| Free ZID | 2.55 ± 11 | — | 2.78 ± 15 | 3.13 ± 55 | — | 2.65 ± 7 | 2.70 ± 8 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the total clearance, CLT (L/h), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration).
| L/h | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 1.39 ± 9 | 1.63 ± 13 | — | 1.62 ± 16 | 1.55 ± 7 | — | 1.74 ± 14 |
| Free ERT | 25.35 ± 6 | 23.75 ± 18 | — | 22.09 ± 16 | 17.83 ± 23 | — | 19.86 ± 19 |
| Total ZID | 7.50 ± 8 | — | 6.98 ± 20 | 6.49 ± 19 | — | 7.80 ± 7 | 7.56 ± 14 |
| Free ZID | 8.28 ± 8 | — | 7.96 ± 20 | 8.54 ± 30 | — | 7.65 ± 8 | 7.89 ± 14 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the apparent volume of distribution at steady state, Vd,ss (L), parameter estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h period following Dose 7 by dose group using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration). This estimate assumes steady state has been achieved.
| liters | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 6.86 ± 5 | 6.73 ± 11 | — | 6.51 ± 11 | 7.17 ± 9 | — | 7.58 ± 10 |
| Free ERT | 105.98 ± 14 | 72.51 ± 16 | — | 69.65 ± 13 | 56.84 ± 30 | — | 61.59 ± 29 |
| Total ZID | 18.04 ± 14 | — | 16.57 ± 18 | 13.88 ± 21 | — | 20.33 ± 7 | 19.35 ± 13 |
| Free ZID | 21.86 ± 10 | — | 18.79 ± 14 | 30.21 ± 197 | — | 20.17 ± 6 | 19.69 ± 13 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the linearity index (ratio) for the total ERT, free ERT, total ZID, and free ZID plasma concentration-time data by dose group. The linearity index is a measure of how linear the relationship is between increase in administered dose and increase in exposure. The linearity index is estimated as AUC(0-tau),ss (Dose 7)/AUC(0-inf) (Dose 1), where the areas under the concentration-time curves from Dose 7 to the end of the dosing interval at steady state and from Dose 1 taken to the limit as the end time becomes arbitrarily large, AUC(0-tau),ss and AUC(0-inf) respectively, are calculated using Phoenix WinNonlin Non-compartmental Analysis with Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration). The AUC(0-tau),ss estimate assumes steady state was reached.
| ratio | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 0.97 ± 4 | 0.97 ± 7 | — | 0.88 ± 11 | 0.89 ± 6 | — | 0.84 ± 9 |
| Free ERT | 0.95 ± 4 | 0.98 ± 4 | — | 0.86 ± 18 | 0.88 ± 9 | — | 0.78 ± 17 |
| Total ZID | 0.94 ± 4 | — | 0.94 ± 13 | 0.96 ± 5 | — | 1.01 ± 8 | 0.89 ± 11 |
| Free ZID | 0.95 ± 5 | — | 0.97 ± 13 | 0.94 ± 26 | — | 1.03 ± 7 | 0.89 ± 13 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the accumulation ratio of the AUC, RAUC (ratio), parameter for the total ERT, free ERT, total ZID, and free ZID plasma concentration-time data by dose group. RAUC is estimated as AUC(0-tau),ss (Dose 7)/AUC(0-24) (Dose 1), where the areas under the concentration-time curves from Dose 7 to the end of the dosing interval at steady state and from Dose 1 extrapolated to 24 h after Dose 1, AUC(0-tau),ss and AUC(0-24) respectively, are calculated using Phoenix WinNonlin Non-compartmental Analysis with the Ke (first-order terminal phase elimination rate constant) acceptance criteria: Rsq_adjusted (adjusted R-squared) = 0.90 and includes at least 3 timepoints after Tmax (time of maximum concentration). The AUC(0-tau),ss estimate assumes steady state was reached.
| ratio | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 0.99 ± 5 | 0.98 ± 7 | — | 0.89 ± 11 | 0.91 ± 6 | — | 0.85 ± 9 |
| Free ERT | 0.96 ± 4 | 0.99 ± 3 | — | 0.87 ± 18 | 0.89 ± 9 | — | 0.79 ± 17 |
| Total ZID | 0.94 ± 4 | — | 0.94 ± 13 | 0.96 ± 5 | — | 1.01 ± 8 | 0.89 ± 11 |
| Free ZID | 0.96 ± 5 | — | 0.97 ± 13 | 0.94 ± 26 | — | 1.03 ± 7 | 0.89 ± 13 |
Geometric mean (GM), and coefficient of variation percentage (CV%) of the accumulation ratio of the Cmax, RCmax (ratio), parameter for the total ERT, free ERT, total ZID, and free ZID plasma concentration-time data by dose group. RCmax is estimated as Cmax (Dose 7)/Cmax (Dose 1), where the Cmax parameters are estimated from the total ERT, free ERT, total ZID, or free ZID plasma concentration-time data over the 24-h periods following Dose 1 and Dose 7, respectively.
| ratio | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Total ERT | 0.92 ± 17 | 1.13 ± 14 | — | 0.97 ± 7 | 1.01 ± 8 | — | 0.88 ± 8 |
| Free ERT | 0.93 ± 11 | 1.12 ± 7 | — | 0.86 ± 37 | 0.99 ± 12 | — | 0.85 ± 28 |
| Total ZID | 0.92 ± 15 | — | 0.96 ± 11 | 0.98 ± 12 | — | 0.98 ± 13 | 0.89 ± 17 |
| Free ZID | 0.90 ± 15 | — | 0.98 ± 11 | 0.85 ± 40 | — | 1.03 ± 10 | 0.89 ± 13 |
Mean and minimum/maximum of the amount of unchanged ERT and the amount of unchanged ZID excreted in urine, Ae,urine (mg), during 0-4 h, 4-8 h, 8-12 h, and 12-24 h following Dose 1 by dose group. Ae,urine parameters are calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
| mg | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Unchanged ERT - 0-4 h | 339.62 (97.70 to 605.00) | 748.60 (573.00 to 995.00) | — | 794.50 (414.00 to 1620.00) | 768.60 (451.00 to 1090.00) | — | 670.13 (87.80 to 1630.00) |
| Unchanged ERT - 4-8 h | 159.23 (74.20 to 268.00) | 275.67 (105.00 to 414.00) | — | 202.67 (163.00 to 272.00) | 713.50 (393.00 to 1850.00) | — | 605.83 (246.00 to 1390.00) |
| Unchanged ERT - 8-12 h | 64.30 (19.80 to 83.80) | 122.38 (58.80 to 204.00) | — | 128.93 (77.50 to 202.00) | 173.50 (128.00 to 227.00) | — | 192.00 (112.00 to 305.00) |
| Unchanged ERT - 12-24 h | 49.80 (25.60 to 66.50) | 84.22 (49.90 to 150.00) | — | 54.38 (19.20 to 106.00) | 149.15 (84.50 to 235.00) | — | 106.95 (58.50 to 158.00) |
| Unchanged ZID - 0-4 h | 544.83 (259.00 to 816.00) | — | 1336.67 (1060.00 to 1620.00) | 1475.00 (1080.00 to 2040.00) | — | 1838.33 (1270.00 to 2110.00) | 1366.50 (248.00 to 2080.00) |
| Unchanged ZID - 4-8 h | 150.55 (62.60 to 277.00) | — | 360.00 (250.00 to 552.00) | 259.00 (149.00 to 314.00) | — | 631.67 (324.00 to 810.00) | 1006.00 (528.00 to 2600.00) |
| Unchanged ZID - 8-12 h | 33.28 (6.88 to 51.30) | — | 80.35 (56.90 to 162.00) | 83.72 (38.20 to 123.00) | — | 143.50 (104.00 to 254.00) | 167.67 (127.00 to 216.00) |
| Unchanged ZID - 12-24 h | 19.93 (13.30 to 24.30) | — | 27.02 (15.10 to 54.10) | 25.53 (18.00 to 37.00) | — | 75.35 (37.60 to 110.00) | 75.83 (21.50 to 176.00) |
Mean and minimum/maximum of the cumulative amount of unchanged ERT and the cumulative amount of unchanged ZID excreted in urine from zero (predose) to 24 h following Dose 1, Ae,urine(0-24) (mg), by dose group. This parameter is calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
| mg | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Unchanged ERT | 594.00 (204.00 to 856.00) | 1085.67 (321.00 to 1490.00) | — | 1181.83 (711.00 to 2190.00) | 1676.67 (1200.00 to 2160.00) | — | 1572.17 (843.00 to 2400.00) |
| Unchanged ZID | 733.17 (370.00 to 922.00) | — | 1798.33 (1470.00 to 1960.00) | 1836.67 (1420.00 to 2420.00) | — | 2688.33 (1820.00 to 3090.00) | 2620.00 (1040.00 to 3180.00) |
Mean and minimum/maximum of the fraction of ERT and the fraction of ZID excreted unchanged in urine, fe,urine (%), during 0-4 h, 4-8 h, 8-12 h, and 12-24 h following Dose 1 by dose group. These fe,urine parameters are calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
| % of dose excreted unchanged | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Unchanged ERT- 0-4 h | 33.96 (9.77 to 60.50) | 37.46 (28.70 to 49.80) | — | 39.75 (20.70 to 81.20) | 25.60 (15.00 to 36.20) | — | 22.33 (2.93 to 54.30) |
| Unchanged ERT- 4-8 h | 15.92 (7.42 to 26.80) | 13.78 (5.27 to 20.70) | — | 10.14 (8.14 to 13.60) | 23.77 (13.10 to 61.60) | — | 20.16 (8.18 to 46.20) |
| Unchanged ERT- 8-12 h | 6.43 (1.98 to 8.38) | 6.12 (2.94 to 10.20) | — | 6.45 (3.88 to 10.10) | 5.79 (4.28 to 7.57) | — | 6.41 (3.74 to 10.20) |
| Unchanged ERT- 12-24 h | 4.98 (2.56 to 6.65) | 4.21 (2.49 to 7.48) | — | 2.72 (0.96 to 5.32) | 4.97 (2.82 to 7.83) | — | 3.57 (1.95 to 5.28) |
| Unchanged ZID - 0-4 h | 54.48 (25.90 to 81.60) | — | 66.70 (52.80 to 81.00) | 73.75 (54.20 to 102.00) | — | 61.25 (42.20 to 70.40) | 45.58 (8.26 to 69.40) |
| Unchanged ZID - 4-8 h | 15.06 (6.26 to 27.70) | — | 17.98 (12.50 to 27.60) | 12.96 (7.45 to 15.70) | — | 21.07 (10.80 to 27.00) | 33.55 (17.60 to 86.80) |
| Unchanged ZID - 8-12 h | 3.33 (0.69 to 5.13) | — | 4.02 (2.84 to 8.11) | 4.18 (1.91 to 6.13) | — | 4.77 (3.45 to 8.46) | 5.60 (4.22 to 7.22) |
| Unchanged ZID - 12-24 h | 1.99 (1.33 to 2.43) | — | 1.35 (0.76 to 2.70) | 1.27 (0.90 to 1.85) | — | 2.51 (1.25 to 3.65) | 2.53 (0.72 to 5.86) |
Mean and minimum/maximum of the fraction of ERT and the fraction of ZID excreted unchanged in urine from zero (predose) to 24 h following Dose 1, fe,urine(0-24) (%), by dose group. This parameter is calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
| % of dose excreted unchanged | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Unchanged ERT | 59.40 (20.40 to 85.60) | 54.32 (16.10 to 74.70) | — | 58.98 (35.50 to 109.00) | 55.85 (40.10 to 71.80) | — | 52.43 (28.10 to 79.90) |
| Unchanged ZID | 73.32 (37.00 to 92.20) | — | 89.82 (73.30 to 97.90) | 91.75 (70.90 to 121.00) | — | 89.58 (60.60 to 103.00) | 87.32 (34.50 to 106.00) |
Geometric mean (GM), and coefficient of variation percentage (CV%) of renal clearance of ERT and ZID from dosing until the last collected concentration for Dose 1 (24 h postdose), CLR(0-24) (mL/h ), by dose group. This parameter is calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
| L/h | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Unchanged ERT | 0.75 ± 61 | 0.78 ± 57 | — | 0.79 ± 41 | 0.76 ± 19 | — | 0.73 ± 42 |
| Unchanged ZID | 4.98 ± 39 | — | 5.88 ± 15 | 5.63 ± 36 | — | 6.95 ± 25 | 5.55 ± 31 |
Mean and minimum/maximum of the amount of unchanged ERT and the amount of unchanged ZID excreted in urine, Ae,urine (mg), during 0-4 h, 4-8 h, 8-12 h, and 12-24 h following Dose 7 by dose group. Ae,urine parameters are calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
| mg | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Unchanged ERT - 0-4 h | 357.83 (208.00 to 525.00) | 702.30 (39.50 to 1270.00) | — | 777.80 (433.00 to 1490.00) | 1010.40 (655.00 to 1530.00) | — | 998.17 (467.00 to 1670.00) |
| Unchanged ERT - 4-8 h | 113.37 (10.10 to 205.00) | 344.17 (132.00 to 911.00) | — | 234.94 (97.70 to 473.00) | 603.40 (186.00 to 1100.00) | — | 417.33 (209.00 to 727.00) |
| Unchanged ERT - 8-12 h | 54.95 (7.16 to 88.10) | 136.54 (21.70 to 198.00) | — | 88.86 (48.10 to 153.00) | 171.80 (137.00 to 217.00) | — | 113.88 (54.00 to 150.00) |
| Unchanged ERT - 12-24 h | 43.04 (26.70 to 68.20) | 29.69 (9.35 to 72.20) | — | 65.46 (55.00 to 81.10) | 113.98 (85.60 to 159.00) | — | 96.03 (61.50 to 167.00) |
| Unchanged ZID - 0-4 h | 624.50 (383.00 to 824.00) | — | 1210.33 (691.00 to 1570.00) | 1465.00 (1465.00 to 1640.00) | — | 1855.00 (1090.00 to 2200.00) | 1870.00 (1320.00 to 2280.00) |
| Unchanged ZID - 4-8 h | 110.20 (7.22 to 173.00) | — | 302.00 (302.00 to 302.00) | 246.00 (219.00 to 307.00) | — | 556.83 (403.00 to 689.00) | 654.33 (253.00 to 1170.00) |
| Unchanged ZID - 8-12 h | 27.93 (3.55 to 45.10) | — | 45.58 (23.10 to 55.40) | 62.98 (40.20 to 93.60) | — | 175.00 (138.00 to 212.00) | 113.78 (27.70 to 160.00) |
| Unchanged ZID - 12-24 h | 14.75 (7.36 to 25.40) | — | 62.37 (18.70 to 124.00) | 32.48 (13.30 to 44.80) | — | 67.67 (45.30 to 84.20) | 59.50 (34.00 to 85.60) |
Mean and minimum/maximum of the cumulative amount of unchanged ERT and the cumulative amount of unchanged ZID excreted in urine from zero (predose) to 24 h following Dose 7, Ae,urine(0-24) (mg), by dose group. This parameter is calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
| mg | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Unchanged ERT | 552.83 (325.00 to 778.00) | 1067.33 (340.00 to 1700.00) | — | 1166 (652.00 to 2200.00) | 1898.00 (1060.00 to 3000.00) | — | 1624.50 (887.00 to 2320.00) |
| Unchanged ZID | 770.17 (495.00 to 1030.00) | — | 1080.00 (1080.00 to 1080.00) | 1808.33 (1580.00 to 1970.00) | — | 2656.67 (1770.00 to 2930.00) | 2700.00 (2200.00 to 3070.00) |
Mean and minimum/maximum of the fraction of ERT and the fraction of ZID excreted unchanged in urine, fe,urine (%), during 0-4 h, 4-8 h, 8-12 h, and 12-24 h following Dose 7 by dose group. These fe,urine parameters are calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
| % of dose excreted unchanged | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Unchanged ERT - 0-4 h | 35.78 (20.80 to 52.50) | 35.09 (1.97 to 63.30) | — | 38.94 (21.70 to 74.60) | 33.68 (21.80 to 51.00) | — | 33.28 (15.60 to 55.80) |
| Unchanged ERT - 4-8 h | 11.34 (1.01 to 20.50) | 17.19 (6.62 to 45.50) | — | 11.72 (4.89 to 23.60) | 20.08 (6.19 to 36.50) | — | 13.91 (6.96 to 24.20) |
| Unchanged ERT - 8-12 h | 5.50 (0.72 to 8.81) | 6.83 (1.08 to 9.91) | — | 4.45 (2.41 to 7.67) | 5.73 (4.57 to 7.23) | — | 3.80 (1.80 to 5.01) |
| Unchanged ERT - 12-24 h | 4.30 (2.67 to 6.82) | 1.48 (0.47 to 3.61) | — | 3.27 (2.75 to 4.06) | 3.80 (2.85 to 5.30) | — | 3.20 (2.05 to 5.56) |
| Unchanged ZID - 0-4 h | 62.45 (38.30 to 82.40) | — | 60.40 (34.50 to 78.40) | 73.27 (62.60 to 82.10) | — | 61.85 (36.40 to 73.40) | 62.38 (44.00 to 76.00) |
| Unchanged ZID - 4-8 h | 11.02 (0.72 to 17.30) | — | 15.10 (15.10 to 15.10) | 12.28 (11.00 to 15.30) | — | 18.55 (13.40 to 23.00) | 21.84 (8.43 to 39.10) |
| Unchanged ZID - 8-12 h | 2.79 (0.36 to 4.51) | — | 2.28 (1.16 to 2.77) | 3.15 (2.01 to 4.68) | — | 5.84 (4.61 to 7.05) | 3.79 (0.92 to 5.34) |
| Unchanged ZID - 12-24 h | 1.48 (0.74 to 2.54) | — | 3.12 (0.93 to 6.20) | 1.63 (0.67 to 2.24) | — | 2.26 (1.51 to 2.81) | 1.98 (1.13 to 2.85) |
Mean and minimum/maximum of the fraction of ERT and the fraction of ZID excreted unchanged in urine from zero (predose) to 24 h following Dose 7, fe,urine(0-24) (%), by dose group. This parameter is calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
| % of dose excreted unchanged | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Unchanged ERT | 55.28 (32.50 to 77.80) | 53.35 (17.00 to 84.90) | — | 58.36 (32.60 to 110.00) | 63.28 (35.50 to 100.00) | — | 54.20 (29.60 to 77.40) |
| Unchanged ZID | 77.02 (49.50 to 103.00) | — | 53.80 (53.80 to 53.80) | 90.35 (78.80 to 98.50) | — | 88.48 (59.00 to 97.50) | 89.93 (73.30 to 102.00) |
Geometric mean (GM), and coefficient of variation percentage (CV%) of renal clearance of ERT and ZID from dosing until the last collected concentration for Dose 7 (24 h postdose), CLR(0-24) (mL/h), by dose group. This parameter is calculated using a combination of Phoenix WinNonlin and SAS version 9.4 or above.
| L/h | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g |
|---|---|---|---|---|---|---|---|
| Unchanged ERT | 0.74 ± 28 | 0.78 ± 53 | — | 0.84 ± 48 | 0.92 ± 37 | — | 0.9 ± 44 |
| Unchanged ZID | 5.59 ± 35 | — | 4.68 ± NA | 5.84 ± 25 | — | 6.8 ± 25 | 6.77 ± 12 |
Collected over AEs were documented from the time of starting study drug administration through the time of Final Visit (Day 11 + 3 days). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Cohort 1 - WCK 6777 2 g | 0/6 (0%) | 0/6 (0%) | 6/6 (100%) |
| Cohort 2 - ERT 2 g | 0/6 (0%) | 0/6 (0%) | 6/6 (100%) |
| Cohort 3 - ZID 2 g | 0/6 (0%) | 0/6 (0%) | 5/6 (83.3%) |
| Cohort 4 - WCK 6777 4 g | 0/6 (0%) | 0/6 (0%) | 5/6 (83.3%) |
| Cohort 5 - ERT 3 g | 0/6 (0%) | 0/6 (0%) | 4/6 (66.7%) |
| Cohort 6 - ZID 3 g | 0/6 (0%) | 0/6 (0%) | 2/6 (33.3%) |
| Cohort 7 - WCK 6777 6 g | 0/6 (0%) | 0/6 (0%) | 4/6 (66.7%) |
| Placebo | 0/10 (0%) | 0/10 (0%) | 9/10 (90%) |
| Event | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g | Placebo |
|---|---|---|---|---|---|---|---|---|
| Infusion site erythemaGeneral disorders | 0/6 | 2/6 | 3/6 | 1/6 | 1/6 | 1/6 | 2/6 | 1/10 |
| DiarrhoeaGastrointestinal disorders | 0/6 | 2/6 | 0/6 | 1/6 | 0/6 | 0/6 | 1/6 | 0/10 |
| NauseaGastrointestinal disorders | 2/6 | 0/6 | 0/6 | 0/6 | 1/6 | 0/6 | 0/6 | 1/10 |
| Infusion site extravasationGeneral disorders | 1/6 | 0/6 | 0/6 | 2/6 | 2/6 | 0/6 | 1/6 | 3/10 |
| Infusion site painGeneral disorders | 1/6 | 2/6 | 1/6 | 0/6 | 0/6 | 0/6 | 0/6 | 0/10 |
| Injection site haemorrhageGeneral disorders | 0/6 | 0/6 | 0/6 | 0/6 | 1/6 | 0/6 | 2/6 | 0/10 |
| Infusion site haemorrhageGeneral disorders | 0/6 | 0/6 | 0/6 | 1/6 | 0/6 | 0/6 | 0/6 | 3/10 |
| Infusion site swellingGeneral disorders | 0/6 | 1/6 | 1/6 | 0/6 | 0/6 | 0/6 | 1/6 | 2/10 |
| Body temperature increasedInvestigations | 0/6 | 0/6 | 0/6 | 0/6 | 0/6 | 0/6 | 0/6 | 2/10 |
| HeadacheNervous system disorders | 1/6 | 1/6 | 1/6 | 0/6 | 1/6 | 0/6 | 0/6 | 2/10 |
| Age, Continuous(years) | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g | Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|
| Mean | 33.7 ± 7.3 | 35.2 ± 9.2 | 32.3 ± 9.5 | 33.2 ± 7.0 | 33.6 ± 7.9 | 37.3 ± 5.6 | 29.2 ± 9.0 | 30.7 ± 6.7 | 33.0 ± 7.6 |
| Sex: Female, Male(Participants) | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g | Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|
| Female | 2 | 3 | 2 | 3 | 2 | 2 | 2 | 4 | 20 |
| Male | 4 | 3 | 4 | 3 | 5 | 5 | 4 | 6 | 34 |
| Ethnicity (NIH/OMB)(Participants) | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g | Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|
| Hispanic or Latino | 2 | 1 | 0 | 1 | 2 | 1 | 0 | 1 | 8 |
| Not Hispanic or Latino | 4 | 5 | 6 | 5 | 5 | 6 | 6 | 9 | 46 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g | Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 |
| Black or African American | 5 | 4 | 2 | 1 | 2 | 2 | 5 | 7 | 28 |
| White | 0 | 2 | 4 | 5 | 4 | 5 | 1 | 2 | 23 |
| More than one race | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| BMI(kg/m2) | Cohort 1 - WCK 6777 2 g | Cohort 2 - ERT 2 g | Cohort 3 - ZID 2 g | Cohort 4 - WCK 6777 4 g | Cohort 5 - ERT 3 g | Cohort 6 - ZID 3 g | Cohort 7 - WCK 6777 6 g | Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|
| Mean | 27.08 ± 2.93 | 28.57 ± 2.05 | 25.18 ± 3.38 | 27.63 ± 2.85 | 23.83 ± 1.62 | 27.27 ± 2.76 | 24.05 ± 4.36 | 26.87 ± 2.82 | 26.32 ± 3.15 |
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National Institute of Allergy and Infectious Diseases (NIAID)