CompletedNCT05981365Updated Nov 22, 2024Results posted

Voxelotor CYP and Transporter Cocktail Interaction Study

A Phase 1 interventional study of Voxelotor and Bupropion in Sickle Cell Disease, sponsored by Pfizer. Completed at 1 site in United States. Open to participants aged 18 Years to 55 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-11-22.

Sponsored by Pfizer · Phase 1, Interventional, and Basic science

Phase: Phase 1
Study type: Interventional
Enrollment: 44
Allocation: Non-randomized
Ages: 18 Years to 55 Years
Sex: All

Study summary

This research study is examining multiple doses of voxelotor (a study drug intended for treatment of sickle cell disease) and how it interacts with additional substrates (substrates are drugs or other substances that are metabolized by cytochrome enzymes. The substrates used in this study are FDA approved medications). The study will help to determine the safety and tolerability of the study drugs taken together, as well as the pharmacokinetics (PK) on how your body processes and responds to the combination of the study drug and substrates. Although these drugs are FDA approved, their use in this study is experimental.

Read the detailed description

This is an open-label, fixed-sequence, 2-period evaluation study. This means the study doctor and participants in the study will know what study drugs they are taking. There will be approximately 46 healthy male and female participants between the ages of 18 - 55. There will be two parts of the study: parts A and B.

Part A will consist of 26 healthy male and female participants (at least 20% African American). For Part A, participant involvement is expected to last approximately 81 days, including a 33-day screening period and a 48-day on study period (consisting of 2 study treatment periods, a washout period lasting 7 to 14 days, and the Follow-up visit).

Part B will consist of 20 healthy male and female participants (at least 20% African American). For Part B, participant involvement is expected to last approximately 68 days, including a 33-day screening period and a 35-day on study period (consisting of 2 study treatment periods, a washout period lasting 7 to 14 days, and the Follow-up visit).

You will only be allowed to be in one part of the study.

Conditions studied

Sickle Cell Disease

Browse trials for

Anemia, Sickle Cell 1,103

Keywords

Drug drug interaction

In context

Anemia, Sickle Cell

1,103 studies on the registry are indexed under Anemia, Sickle Cell; 235 are open to participants now.

This study's enrollment of 44 is close to the median of 40 across 750 interventional studies indexed under Anemia, Sickle Cell.

Browse Anemia, Sickle Cell studies →

Lead sponsor

Pfizer is the lead sponsor of 3,244 studies on the registry; 139 are open to participants now.

Of its 582 completed or terminated interventional studies of FDA-regulated products, 381 (65%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 55 Years
Sexes eligible: All
Accepts healthy volunteers: Yes

Inclusion criteria

1. Males or females ≥ 18 and ≤ 55 years of age inclusive, at the time of signing the informed consent.
  1. No clinically significant findings as assessed by review of medical and surgical history, vital signs assessments, 12-lead electrocardiograms (ECG), physical examination, and clinical laboratory evaluations conducted at screening and day of admission. A single repeat measurement/test may be performed to confirm eligibility based upon initial vital signs, ECG, or clinical laboratory tests abnormalities.
  1. Body mass Index (BMI) ≥ 18.0 and ≤ 30.0 kg/m2, and body weight ≥ 50 kg at screening and Period 1 Day -1. BMI = weight (kg)/(height [m])2
  1. Females of childbearing potential must agree to use a highly effective method of contraception or practice abstinence from 2 weeks prior to study start through 30 days after the last dose of study drug. A highly effective method of contraception is defined as one that results in a low documented failure rate when used consistently and correctly such as: condom plus use of an intrauterine device; intrauterine system or hormonal method of contraception (oral, injected, implanted, or transdermal) for their female partner; or sexual abstinence. Males must be surgically sterilized, or agree to practice true abstinence, or use acceptable contraception if sexually active with a female partner of childbearing potential, throughout the study, and for at least 30 days after the last dose of study drug.
  1. Males must agree not to donate sperm during the study and for 30 days following last dose of study drug.

Exclusion criteria

Exclusion Criteria:

Positive pregnancy test or is lactating.
History or presence of clinically significant allergic diseases (except for untreated,
asymptomatic, seasonal allergies) at time of screening in the opinion of the Investigator.
History or presence of conditions which, in the opinion of the Investigator, are known to interfere with the absorption, distribution, metabolism, or excretion of drugs, such as previous surgery on the gastrointestinal tract (including removal of parts of the stomach, bowel, liver, or pancreas). Participants who have a history of cholecystectomy and appendectomy are eligible for enrollment.
Any signs and/or symptoms of acute illness at screening or Day -1.
Abnormal ECG in any of the single ECGs collected at screening or Day -1, including QTcF > 430 msec for males and > 450 msec for females, or any cardiac rhythm other than sinus rhythm that is interpreted by the Investigator to be clinically significant. A single repeat measurement may be performed to re-evaluate ECG abnormalities (ie, to confirm that a participant is eligible). All the single ECGs must be not clinically significant to qualify for enrollment into the study.
Resting bradycardia (HR \< 45 bpm) or resting tachycardia (HR > 100 bpm) at screening or Day -1. A single repeat measurement may be performed to re-evaluate vital signs abnormalities(ie, to confirm that a participant is ineligible). Each of the readings must be not clinically significant to qualify for enrollment into the study.
Hypertension, defined as resting (supine) systolic blood pressure (BP) > 140 mmHg or resting diastolic BP > 90 mmHg at screening or Day -1. A single repeat measurement may be performed to re-evaluate vital signs abnormalities (ie, to confirm that a participant is eligible). Each of the readings must be not clinically significant to qualify for enrollment into the study.
Use of prescription medications (with the exception of contraception), any over the counter drugs including herbal preparations including St. John's wort or dietary supplements, or any drugs that induce or inhibit study drug specific CYP450(s) within 14 days or 5 half-lives, whichever is longer, prior to Day -1, or requires continuing use during study participation.
Prior exposure to voxelotor/Oxbryta® within the past month.
Clinically significant anemia, or has donated blood or blood components exceeding 400 mL within 90 days prior to screening.
Positive screen for human immunodeficiency virus 1 (HIV-1) and HIV -2 antibodies, hepatitis A virus antibody, hepatitis B surface antigen, or hepatitis C virus antibody.
History or presence of contraindication to the use of midazolam including but not limited to hypersensitivity to benzodiazepines or formulation ingredients, acute narrow-angle glaucoma, myasthenia gravis, severe respiratory insufficiency, or sleep apnea syndrome.
Poor CYP2C9 or CYP2C19 metabolizer (determined at screening or available historical data).
Participant has an allergy or sensitivity to voxelotor, bupropion, repaglinide, flurbiprofen, omeprazole, or midazolam.
Part B only
History of statin-induced myopathy or serious hypersensitivity reaction to other 3-hydroxy-3-methylglutaryl coenzyme A, reductase inhibitors (statins).
Heterozygous or homozygous variant allele carriers of SLCO1B1 (c.521T>C, rs4149056), encoding the hepatic uptake transporter OATP1B1, resulting in decreased transport activity.
Participant has an allergy or sensitivity to voxelotor, metformin, furosemide, or rosuvastatin.

Study design

Phase: Phase 1
Primary purpose: Basic science
Allocation: Non-randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 44 participants (actual)

Study arms

Experimental
Part A
To evaluate the effect of multiple doses of voxelotor on the plasma pharmacokinetics (PK) of a single dose of bupropion, repaglinide, flurbiprofen, omeprazole, and midazolam
Drug: Voxelotor · Drug: Bupropion · Drug: Repaglinide · Drug: Flurbiprofen · Drug: Omeprazole · Drug: Midazolam
Experimental
Part B
To evaluate the effect of multiple doses of voxelotor on the plasma PK of a single dose of metformin, furosemide, and rosuvastatin
Drug: Voxelotor · Drug: Metformin · Drug: Furosemide · Drug: Rosuvastatin

Interventions

DrugVoxelotor
Drug drug interaction
Also known as: Oxbryta
DrugBupropion
Drug drug interaction
Also known as: Wellbutrin
DrugRepaglinide
Drug drug interaction
Also known as: Prandin
DrugFlurbiprofen
Drug drug interaction
Also known as: Ansaid
DrugOmeprazole
Drug drug interaction
Also known as: Prilosec
DrugMidazolam
Drug drug interaction
Also known as: Dormicum
DrugMetformin
Drug drug interaction
Also known as: Glucophage
DrugFurosemide
Drug drug interaction
Also known as: Lasix
DrugRosuvastatin
Drug drug interaction
Also known as: Crestor

What researchers measure

Primary outcomes

Part A: Maximum Observed Plasma Concentration (Cmax) for Bupropion
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Part A: Cmax for Repaglinide
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively
Part A: Cmax for Flurbiprofen
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: Cmax for Omeprazole
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: Cmax for Midazolam
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: Area Under the Plasma Concentration-Time Curve From Time Zero (0) to the Time of the Last Quantifiable Concentration (AUCt) for Bupropion
AUCt was calculated using the linear/log trapezoidal rule.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Part A: AUCt for Repaglinide
AUCt was calculated using the linear/log trapezoid rule.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively
Part A: AUCt for Flurbiprofen
AUCt was calculated using the linear/log trapezoid rule.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: AUCt for Omeprazole
AUCt was calculated using the linear/log trapezoid rule.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: AUCt for Midazolam
AUCt was calculated using the linear/log trapezoid rule.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) for Bupropion
AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Part A: AUCinf for Repaglinide
AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively
Part A: AUCinf for Flurbiprofen
AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: AUCinf for Omeprazole
AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: AUCinf for Midazolam
AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part B: Cmax for Metformin
Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Part B: Cmax for Furosemide
Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Part B: Cmax for Rosuvastatin
Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Part B: AUCt for Metformin
AUCt was calculated using the linear/log trapezoid rule.
Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Part B: AUCt for Furosemide
AUCt was calculated using the linear/log trapezoid rule.
Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Part B: AUCt for Rosuvastatin
AUCt was calculated using the linear/log trapezoid rule.
Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Day 1 and Day 4 for Treatment A and Treatment C, respectively
Part B: AUCinf for Metformin
AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Part B: AUCinf for Furosemide
AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Part B: AUCinf for Rosuvastatin
AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Secondary outcomes

Part A: Cmax for 6-Hydroxybupropion
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Part A: Cmax for 5-Hydroxyomeprazole
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: Cmax for 1-Hydroxymidazolam
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: AUCt for 6-Hydroxybupropion
AUCt was calculated using the linear/log trapezoid rule.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Part A: AUCt for 5-Hydroxyomeprazole
AUCt was calculated using the linear/log trapezoid rule.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: AUCt for 1-Hydroxymidazolam
AUCt was calculated using the linear/log trapezoid rule.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: AUCinf for 6-Hydroxybupropion
AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Part A: AUCinf for 5-Hydroxyomeprazole
AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: AUCinf for 1-Hydroxymidazolam
AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: Time at Which Cmax Was Observed (Tmax) for Bupropion
The time that Cmax was observed.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Part A: Tmax for 6-Hydroxybupropion
The time that Cmax was observed for 6-Hydroxybupropion.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Part A: Tmax for Repaglinide
The time that Cmax was observed for Repaglinide.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively
Part A: Tmax for Flurbiprofen
The time that Cmax was observed for Flurbiprofen.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: Tmax for Omeprazole
The time that Cmax was observed for Omeprazole.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: Tmax for 5-Hydroxyomeprazole
The time that Cmax was observed for 5-Hydroxyomeprazole.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: Tmax for Midazolam
The time that Cmax was observed for Midazolam.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: Tmax for 1-Hydroxymidazolam
The time that Cmax was observed for 1-Hydroxymidazolam.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: Terminal Elimination Half-life (T½) for Bupropion
T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Part A: t1/2 6-Hydroxybupropion
T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Part A: T1/2 for Repaglinide
T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively
Part A: T1/2 for Flurbiprofen
T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: T1/2 for Omeprazole
T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: T1/2 for 5-Hydroxyomeprazole
T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: T1/2 for Midazolam
T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: T1/2 for 1-Hydroxymidazolam
T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight (AUCt M/P) for 6-Hydroxybupropion/Bupropion
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for 5-Hydroxyomeprazole/Omeprazole
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for Hydroxymidazolam/Midazolam
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Part B: Tmax for Metformin
Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Part B: Tmax for Furosemide
Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Part B: Tmax for Rosuvastatin
Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Part B: T½ for Metformin
T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Part B: T½ for Furosemide
T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Part B: T½ for Rosuvastatin
T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.
Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Other outcomes

Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not thought to be related to the investigational product. TEAE: any event that was not present before exposure to study drug (voxelotor or cocktail drugs \[probe substrates\]) or any event already present that worsened in either intensity or frequency after exposure to study drug. An SAE was defined as an AE that at any dose resulted in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or disability; a congenital anomaly/birth defect; other important medical events.
Time frame: From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days)
Part B: Number of Participants With TEAEs and SAEs
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not thought to be related to the investigational product. TEAE: any event that was not present before exposure to study drug (voxelotor or cocktail drugs \[probe substrates\]) or any event already present that worsened in either intensity or frequency after exposure to study drug. An SAE was defined as an AE that at any dose resulted in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or disability; a congenital anomaly/birth defect; other important medical events.
Time frame: From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days)
Part A: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests
The following laboratory parameters were assessed: hematology: hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, red blood cell count, neutrophils, monocytes, lymphocytes, basophils and eosinophils. coagulation: prothrombin time, partial thromboplastin time, international normalized ratio. Serum Chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen, lactate dehydrogenase. Urinalysis: ketones, pH, protein, blood glucose, bilirubin, chloride, bicarbonate, phosphorous, potassium was assessed. Clinical significance of laboratory abnormalities was determined by investigator.
Time frame: From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days)
Part A: Number of Participants With Clinically Significant Abnormalities in Physical Examinations
A complete physical examination included cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight were also measured and recorded. Clinical significance of physical examinations was determined by investigator.
Time frame: From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days)
Part A: Number of Participants With Clinically Significant Abnormalities in Vital Signs
Vital signs included oral temperature, heart rate, respiratory rate (breaths per minute), and blood pressure. Blood pressure and heart rate were measured in a supine position using completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Clinical significance of vital signs was determined by investigator.
Time frame: From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days)
Part B: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests
The following laboratory parameters were assessed: hematology: hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, red blood cell count, neutrophils, monocytes, lymphocytes, basophils and eosinophils. coagulation: prothrombin time, partial thromboplastin time, international normalized ratio. Serum Chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen, lactate dehydrogenase. Urinalysis: ketones, pH, protein, blood glucose, bilirubin, chloride, bicarbonate, phosphorous, potassium was assessed. Clinical significance of laboratory abnormalities was determined by investigator.
Time frame: From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days)
Part B: Number of Participants With Clinically Significant Abnormalities in Physical Examinations
A complete physical examination included cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight were also measured and recorded. Clinical significance of physical examinations was determined by investigator.
Time frame: From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days)
Part B: Number of Participants With Clinically Significant Abnormalities in Vital Signs
Vital signs included oral temperature, heart rate, respiratory rate (breaths per minute), and blood pressure. Blood pressure and heart rate were measured in a supine position using completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Clinical significance of vital signs was determined by investigator.
Time frame: From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days)

Results

Posted Nov 22, 2024

Participant flow

Period 1

Participant flow — Period 1
Milestone	Part A:Treatment Sequence ABCDEFG	Part B: Treatment Sequence ABCD
Started	26	18
Completed	25	18
Not completed	1	0
Withdrew: Adverse event	1	0

Washout Period

Participant flow — Washout Period
Milestone	Part A:Treatment Sequence ABCDEFG	Part B: Treatment Sequence ABCD
Started	25	18
Completed	25	18
Not completed	0	0

Period 2

Participant flow — Period 2
Milestone	Part A:Treatment Sequence ABCDEFG	Part B: Treatment Sequence ABCD
Started	25	18
Completed	25	18
Not completed	0	0

Outcome measures

PrimaryPart A: Maximum Observed Plasma Concentration (Cmax) for Bupropion

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Reported as:: Geometric mean · Nanogram per milliliter (ng/mL)

Part A: Maximum Observed Plasma Concentration (Cmax) for Bupropion
Nanogram per milliliter (ng/mL)	Part A: Period 1: Treatment A	Part A: Period 2: Treatment D	Part A: Period 2: Treatment G
Part A: Maximum Observed Plasma Concentration (Cmax) for Bupropion	160.5 ± 31	201.3 ± 35	191.1 ± 36

Statistical analysis

Part A: Period 1: Treatment A vs Part A: Period 2: Treatment D · Ratio of geometric ls means: 1.2629 · 90% CI 1.1673 to 1.3663
Part A: Period 1: Treatment A vs Part A: Period 2: Treatment G · Ratio of geometric ls means: 1.1845 · 95% CI 1.0758 to 1.3042

PrimaryPart A: Cmax for Repaglinide

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively
Reported as:: Geometric mean · ng/ml

Part A: Cmax for Repaglinide
ng/ml	Part A: Period 1: Treatment B	Part A: Period 2: Treatment F
Part A: Cmax for Repaglinide	10.85 ± 41	12.89 ± 37

Statistical analysis

Part A: Period 1: Treatment B vs Part A: Period 2: Treatment F · Ratio of geometric ls means: 1.1929 · 90% CI 1.0215 to 1.3930

PrimaryPart A: Cmax for Flurbiprofen

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Geometric mean · ng/ml

Part A: Cmax for Flurbiprofen
ng/ml	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: Cmax for Flurbiprofen	6923 ± 25	7820 ± 20

Statistical analysis

Part A: Period 1: Treatment A vs Part A: Period 2: Treatment E · Ratio of geometric ls means: 1.1311 · 90% CI 1.0496 to 1.2189

PrimaryPart A: Cmax for Omeprazole

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Geometric mean · ng/ml

Part A: Cmax for Omeprazole
ng/ml	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: Cmax for Omeprazole	458.1 ± 58	374.3 ± 57

Statistical analysis

Part A: Period 1: Treatment A vs Part A: Period 2: Treatment E · Ratio of geometric ls means: 0.8228 · 90% CI 0.6992 to 0.9683

PrimaryPart A: Cmax for Midazolam

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Geometric mean · ng/ml

Part A: Cmax for Midazolam
ng/ml	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: Cmax for Midazolam	10.33 ± 38	15.99 ± 23

Statistical analysis

Part A: Period 1: Treatment A vs Part A: Period 2: Treatment E · Ratio of geometric ls means: 1.5738 · 90% CI 1.4523 to 1.7054

PrimaryPart A: Area Under the Plasma Concentration-Time Curve From Time Zero (0) to the Time of the Last Quantifiable Concentration (AUCt) for Bupropion

AUCt was calculated using the linear/log trapezoidal rule.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Reported as:: Geometric mean · Hour* nanogram/milliliter (h*ng/mL)

Part A: Area Under the Plasma Concentration-Time Curve From Time Zero (0) to the Time of the Last Quantifiable Concentration (AUCt) for Bupropion
Hour* nanogram/milliliter (h*ng/mL)	Part A: Period 1 Treatment A	Part A: Period 2: Treatment D	Part A: Period 2: Treatment G
Part A: Area Under the Plasma Concentration-Time Curve From Time Zero (0) to the Time of the Last Quantifiable Concentration (AUCt) for Bupropion	845.3 ± 29	963.9 ± 28	812.1 ± 28

Statistical analysis

Part A: Period 1 Treatment A vs Part A: Period 2: Treatment D · Ratio of geometric ls means: 1.1491 · 90% CI 1.0807 to 1.2220
Part A: Period 1 Treatment A vs Part A: Period 2: Treatment G · Ratio of geometric ls means: 0.9494 · 90% CI 0.8759 to 1.0291

PrimaryPart A: AUCt for Repaglinide

AUCt was calculated using the linear/log trapezoid rule.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively
Reported as:: Geometric mean · h*ng/mL

Part A: AUCt for Repaglinide
h*ng/mL	Part A: Period 1: Treatment B	Part A: Period 2: Treatment F
Part A: AUCt for Repaglinide	15.47 ± 40	20.59 ± 34

Statistical analysis

Part A: Period 1: Treatment B vs Part A: Period 2: Treatment F · Ratio of geometric ls means: 1.3316 · 90% CI 1.2558 to 1.4121

PrimaryPart A: AUCt for Flurbiprofen

AUCt was calculated using the linear/log trapezoid rule.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Geometric mean · h*ng/mL

Part A: AUCt for Flurbiprofen
h*ng/mL	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: AUCt for Flurbiprofen	39639 ± 26	44940 ± 24

Statistical analysis

Part A: Period 1: Treatment A vs Part A: Period 2: Treatment E · Ratio of geometric ls means: 1.1282 · 90% CI 1.0700 to 1.1896

PrimaryPart A: AUCt for Omeprazole

AUCt was calculated using the linear/log trapezoid rule.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Geometric mean · h*ng/mL

Part A: AUCt for Omeprazole
h*ng/mL	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: AUCt for Omeprazole	889.4 ± 62	721.8 ± 68

Statistical analysis

Part A: Period 1: Treatment A vs Part A: Period 2: Treatment E · Ratio of geometric ls means: 0.8047 · 90% CI 0.7173 to 0.9027

PrimaryPart A: AUCt for Midazolam

AUCt was calculated using the linear/log trapezoid rule.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Geometric mean · h*ng/mL

Part A: AUCt for Midazolam
h*ng/mL	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: AUCt for Midazolam	25.78 ± 42	52.58 ± 27

Statistical analysis

Part A: Period 1: Treatment A vs Part A: Period 2: Treatment E · Ratio of geometric ls means: 2.0611 · 90% CI 1.8789 to 2.2609

PrimaryPart A: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) for Bupropion

AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Reported as:: Geometric mean · Hour*nanogram/milliliter

Part A: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) for Bupropion
Hour*nanogram/milliliter	Part A: Period 1 Treatment A	Part A: Period 2: Treatment D	Part A: Period 2: Treatment G
Part A: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) for Bupropion	883.3 ± 30	985.4 ± 28	839.1 ± 28

Statistical analysis

Part A: Period 1 Treatment A vs Part A: Period 2: Treatment G · Ratio of geometric ls means: 1.1374 · 90% CI 1.0672 to 1.2122
Part A: Period 1 Treatment A vs Part A: Period 2: Treatment G · Ratio of geometric ls means: 0.9371 · 90% CI 0.8643 to 1.0162

PrimaryPart A: AUCinf for Repaglinide

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively
Reported as:: Geometric mean · h*ng/mL

Part A: AUCinf for Repaglinide
h*ng/mL	Part A: Period 1: Treatment B	Part A: Period 2: Treatment F
Part A: AUCinf for Repaglinide	16.49 ± 40	21.74 ± 33

Statistical analysis

Part A: Period 1: Treatment B vs Part A: Period 2: Treatment F · Ratio of geometric ls means: 1.2713 · 90% CI 1.1939 to 1.3538

PrimaryPart A: AUCinf for Flurbiprofen

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Geometric mean · h*ng/mL

Part A: AUCinf for Flurbiprofen
h*ng/mL	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: AUCinf for Flurbiprofen	40047 ± 26	45361 ± 25

Statistical analysis

Part A: Period 1: Treatment A vs Part A: Period 2: Treatment E · Ratio of geometric ls means: 1.1270 · 90% CI 1.0688 to 1.1883

PrimaryPart A: AUCinf for Omeprazole

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Geometric mean · h*ng/mL

Part A: AUCinf for Omeprazole
h*ng/mL	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: AUCinf for Omeprazole	932.3 ± 62	743.1 ± 69

Statistical analysis

Part A: Period 1: Treatment A vs Part A: Period 2: Treatment E · Ratio of geometric ls means: 0.7973 · 90% CI 0.7039 to 0.9031

PrimaryPart A: AUCinf for Midazolam

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Geometric mean · h*ng/mL

Part A: AUCinf for Midazolam
h*ng/mL	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: AUCinf for Midazolam	27.15 ± 40	54.42 ± 28

Statistical analysis

Part A: Period 1: Treatment A vs Part A: Period 2: Treatment E · Ratio of geometric ls means: 2.0260 · 90% CI 1.8496 to 2.2193

PrimaryPart B: Cmax for Metformin

Time frame:: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Reported as:: Geometric mean · ng/mL

Part B: Cmax for Metformin
ng/mL	Part B: Period 1: Treatment A	Part B: Period 2: Treatment C
Part B: Cmax for Metformin	55.84 ± 35	44.17 ± 36

Statistical analysis

Part B: Period 1: Treatment A vs Part B: Period 2: Treatment C · Ratio of geometric ls means: 0.7909 · 90% CI 0.7160 to 0.8737

PrimaryPart B: Cmax for Furosemide

Time frame:: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Reported as:: Geometric mean · ng/mL

Part B: Cmax for Furosemide
ng/mL	Part B: Period 1: Treatment A	Part B: Period 2: Treatment C
Part B: Cmax for Furosemide	48.58 ± 32	52.62 ± 35

Statistical analysis

Part B: Period 1: Treatment A vs Part B: Period 2: Treatment C · Ratio of geometric ls means: 1.0831 · 90% CI 0.9723 to 1.2065

PrimaryPart B: Cmax for Rosuvastatin

Time frame:: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Reported as:: Geometric mean · ng/mL

Part B: Cmax for Rosuvastatin
ng/mL	Part B: Period 1: Treatment A	Part B: Period 2: Treatment C
Part B: Cmax for Rosuvastatin	5.545 ± 46	7.286 ± 53

Statistical analysis

Part B: Period 1: Treatment A vs Part B: Period 2: Treatment C · Ratio of geometric ls means: 1.3138 · 90% CI 1.1871 to 1.4541

PrimaryPart B: AUCt for Metformin

AUCt was calculated using the linear/log trapezoid rule.

Time frame:: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Reported as:: Geometric mean · h*ng/mL

Part B: AUCt for Metformin
h*ng/mL	Part B: Period 1: Treatment A	Part B: Period 2: Treatment C
Part B: AUCt for Metformin	303.8 ± 26	241.7 ± 30

Statistical analysis

Part B: Period 1: Treatment A vs Part B: Period 2: Treatment C · Ratio of geometric ls means: 0.7958 · 90% CI 0.7420 to 0.8534

PrimaryPart B: AUCt for Furosemide

AUCt was calculated using the linear/log trapezoid rule.

Time frame:: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Reported as:: Geometric mean · h*ng/mL

Part B: AUCt for Furosemide
h*ng/mL	Part B: Period 1: Treatment A	Part B: Period 2: Treatment C
Part B: AUCt for Furosemide	105.0 ± 28	108.4 ± 33

Statistical analysis

Part B: Period 1: Treatment A vs Part B: Period 2: Treatment C · Ratio of geometric ls means: 1.0322 · 90% CI 0.9531 to 1.1179

PrimaryPart B: AUCt for Rosuvastatin

AUCt was calculated using the linear/log trapezoid rule.

Time frame:: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Day 1 and Day 4 for Treatment A and Treatment C, respectively
Reported as:: Geometric mean · h*ng/mL

Part B: AUCt for Rosuvastatin
h*ng/mL	Part B: Period 1: Treatment A	Part B: Period 2: Treatment C
Part B: AUCt for Rosuvastatin	50.29 ± 46	60.22 ± 45

Statistical analysis

Part B: Period 1: Treatment A vs Part B: Period 2: Treatment C · Ratio of geometric ls means: 1.1975 · 90% CI 1.0972 to 1.3069

PrimaryPart B: AUCinf for Metformin

Time frame:: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Reported as:: Geometric mean · h*ng/mL

Part B: AUCinf for Metformin
h*ng/mL	Part B: Period 1: Treatment A	Part B: Period 2: Treatment C
Part B: AUCinf for Metformin	310.5 ± 25	249.0 ± 29

Statistical analysis

Part B: Period 1: Treatment A vs Part B: Period 2: Treatment C · Ratio of geometric ls means: 0.8018 · 90% CI 0.7472 to 0.8604

PrimaryPart B: AUCinf for Furosemide

Time frame:: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Reported as:: Geometric mean · h*ng/mL

Part B: AUCinf for Furosemide
h*ng/mL	Part B: Period 1: Treatment A	Part B: Period 2: Treatment C
Part B: AUCinf for Furosemide	108.4 ± 29	113.3 ± 30

Statistical analysis

Part B: Period 1: Treatment A vs Part B: Period 2: Treatment C · Ratio of geometric ls means: 1.0630 · 90% CI 0.9888 to 1.1427

PrimaryPart B: AUCinf for Rosuvastatin

Time frame:: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Reported as:: Geometric mean · h*ng/mL

Part B: AUCinf for Rosuvastatin
h*ng/mL	Part B: Period 1: Treatment A	Part B: Period 2: Treatment C
Part B: AUCinf for Rosuvastatin	50.87 ± 45	63.16 ± 43

Statistical analysis

Part B: Period 1: Treatment A vs Part B: Period 2: Treatment C · Ratio of geometric ls means: 1.2197 · 90% CI 1.1114 to 1.3385

SecondaryPart A: Cmax for 6-Hydroxybupropion

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Reported as:: Geometric mean · ng/mL

Part A: Cmax for 6-Hydroxybupropion
ng/mL	Part A: Period 1 Treatment A	Part A: Period 2: Treatment D	Part A: Period 2: Treatment G
Part A: Cmax for 6-Hydroxybupropion	351.1 ± 45	376.3 ± 45	489.1 ± 49

SecondaryPart A: Cmax for 5-Hydroxyomeprazole

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Geometric mean · ng/mL

Part A: Cmax for 5-Hydroxyomeprazole
ng/mL	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: Cmax for 5-Hydroxyomeprazole	179.8 ± 29	216.8 ± 27

SecondaryPart A: Cmax for 1-Hydroxymidazolam

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Geometric mean · ng/ml

Part A: Cmax for 1-Hydroxymidazolam
ng/ml	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: Cmax for 1-Hydroxymidazolam	5.984 ± 44	7.291 ± 28

SecondaryPart A: AUCt for 6-Hydroxybupropion

AUCt was calculated using the linear/log trapezoid rule.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Reported as:: Geometric mean · h*ng/mL

Part A: AUCt for 6-Hydroxybupropion
h*ng/mL	Part A: Period 1 Treatment A	Part A: Period 2: Treatment D	Part A: Period 2: Treatment G
Part A: AUCt for 6-Hydroxybupropion	11529 ± 49	11223 ± 44	13453 ± 53

SecondaryPart A: AUCt for 5-Hydroxyomeprazole

AUCt was calculated using the linear/log trapezoid rule.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Geometric mean · h*ng/mL

Part A: AUCt for 5-Hydroxyomeprazole
h*ng/mL	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: AUCt for 5-Hydroxyomeprazole	504.1 ± 21	611.4 ± 21

SecondaryPart A: AUCt for 1-Hydroxymidazolam

AUCt was calculated using the linear/log trapezoid rule.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Geometric mean · h*ng/mL

Part A: AUCt for 1-Hydroxymidazolam
h*ng/mL	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: AUCt for 1-Hydroxymidazolam	12.73 ± 43	20.07 ± 27

SecondaryPart A: AUCinf for 6-Hydroxybupropion

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Reported as:: Geometric mean · h*ng/mL

Part A: AUCinf for 6-Hydroxybupropion
h*ng/mL	Part A: Period 1 Treatment A	Part A: Period 2: Treatment D	Part A: Period 2: Treatment G
Part A: AUCinf for 6-Hydroxybupropion	11692 ± 47	12407 ± 44	14990 ± 55

SecondaryPart A: AUCinf for 5-Hydroxyomeprazole

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Geometric mean · h*ng/mL

Part A: AUCinf for 5-Hydroxyomeprazole
h*ng/mL	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: AUCinf for 5-Hydroxyomeprazole	510.3 ± 21	615.5 ± 22

SecondaryPart A: AUCinf for 1-Hydroxymidazolam

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Geometric mean · h*ng/mL

Part A: AUCinf for 1-Hydroxymidazolam
h*ng/mL	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: AUCinf for 1-Hydroxymidazolam	12.72 ± 43	20.92 ± 26

SecondaryPart A: Time at Which Cmax Was Observed (Tmax) for Bupropion

The time that Cmax was observed.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Reported as:: Median · Hours

Part A: Time at Which Cmax Was Observed (Tmax) for Bupropion
Hours	Part A: Period 1 Treatment A	Part A: Period 2: Treatment D	Part A: Period 2: Treatment G
Part A: Time at Which Cmax Was Observed (Tmax) for Bupropion	1.500 (1.00 to 3.00)	1.500 (1.00 to 3.00)	1.500 (1.00 to 3.00)

SecondaryPart A: Tmax for 6-Hydroxybupropion

The time that Cmax was observed for 6-Hydroxybupropion.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Reported as:: Median · Hours

Part A: Tmax for 6-Hydroxybupropion
Hours	Part A: Period 1 Treatment A	Part A: Period 2: Treatment D	Part A: Period 2: Treatment G
Part A: Tmax for 6-Hydroxybupropion	3.015 (1.13 to 8.05)	4.000 (2.00 to 8.00)	3.000 (1.50 to 4.00)

SecondaryPart A: Tmax for Repaglinide

The time that Cmax was observed for Repaglinide.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively
Reported as:: Median · Hours

Part A: Tmax for Repaglinide
Hours	Part A: Period 1: Treatment B	Part A: Period 2: Treatment F
Part A: Tmax for Repaglinide	0.500 (0.50 to 1.07)	0.500 (0.50 to 2.00)

SecondaryPart A: Tmax for Flurbiprofen

The time that Cmax was observed for Flurbiprofen.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Median · Hours

Part A: Tmax for Flurbiprofen
Hours	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: Tmax for Flurbiprofen	2.000 (0.50 to 6.00)	1.500 (0.50 to 3.13)

SecondaryPart A: Tmax for Omeprazole

The time that Cmax was observed for Omeprazole.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Median · Hours

Part A: Tmax for Omeprazole
Hours	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: Tmax for Omeprazole	2.000 (1.00 to 4.00)	2.000 (1.00 to 3.13)

SecondaryPart A: Tmax for 5-Hydroxyomeprazole

The time that Cmax was observed for 5-Hydroxyomeprazole.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Median · Hours

Part A: Tmax for 5-Hydroxyomeprazole
Hours	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: Tmax for 5-Hydroxyomeprazole	2.000 (1.00 to 4.02)	2.000 (1.00 to 4.00)

SecondaryPart A: Tmax for Midazolam

The time that Cmax was observed for Midazolam.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Median · Hours

Part A: Tmax for Midazolam
Hours	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: Tmax for Midazolam	1.000 (0.50 to 3.00)	1.000 (0.50 to 1.00)

SecondaryPart A: Tmax for 1-Hydroxymidazolam

The time that Cmax was observed for 1-Hydroxymidazolam.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Median · Hours

Part A: Tmax for 1-Hydroxymidazolam
Hours	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: Tmax for 1-Hydroxymidazolam	1.000 (0.50 to 3.00)	1.000 (0.50 to 1.03)

SecondaryPart A: Terminal Elimination Half-life (T½) for Bupropion

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Reported as:: Mean · Hours

Part A: Terminal Elimination Half-life (T½) for Bupropion
Hours	Part A: Period 1 Treatment A	Part A: Period 2: Treatment D	Part A: Period 2: Treatment G
Part A: Terminal Elimination Half-life (T½) for Bupropion	20.577 ± 2.6082	19.203 ± 2.6331	19.383 ± 2.6591

SecondaryPart A: t1/2 6-Hydroxybupropion

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Reported as:: Mean · Hours

Part A: t1/2 6-Hydroxybupropion
Hours	Part A: Period 1 Treatment A	Part A: Period 2: Treatment D	Part A: Period 2: Treatment G
Part A: t1/2 6-Hydroxybupropion	26.228 ± 5.9780	23.220 ± 4.9391	21.500 ± 4.3406

SecondaryPart A: T1/2 for Repaglinide

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively
Reported as:: Mean · Hours

Part A: T1/2 for Repaglinide
Hours	Part A: Period 1: Treatment B	Part A: Period 2: Treatment F
Part A: T1/2 for Repaglinide	4.684 ± 1.6568	6.242 ± 1.3469

SecondaryPart A: T1/2 for Flurbiprofen

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Mean · Hours

Part A: T1/2 for Flurbiprofen
Hours	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: T1/2 for Flurbiprofen	6.906 ± 1.2545	6.855 ± 1.2666

SecondaryPart A: T1/2 for Omeprazole

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Mean · Hours

Part A: T1/2 for Omeprazole
Hours	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: T1/2 for Omeprazole	0.945 ± 0.3240	0.891 ± 0.2785

SecondaryPart A: T1/2 for 5-Hydroxyomeprazole

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Mean · Hours

Part A: T1/2 for 5-Hydroxyomeprazole
Hours	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: T1/2 for 5-Hydroxyomeprazole	1.455 ± 0.5103	1.387 ± 0.2029

SecondaryPart A: T1/2 for Midazolam

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Mean · Hours

Part A: T1/2 for Midazolam
Hours	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: T1/2 for Midazolam	4.502 ± 1.7340	5.497 ± 0.6465

SecondaryPart A: T1/2 for 1-Hydroxymidazolam

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Mean · Hours

Part A: T1/2 for 1-Hydroxymidazolam
Hours	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: T1/2 for 1-Hydroxymidazolam	3.346 ± 4.0653	3.172 ± 0.9569

SecondaryPart A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight (AUCt M/P) for 6-Hydroxybupropion/Bupropion

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively
Reported as:: Geometric mean · Ratio

Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight (AUCt M/P) for 6-Hydroxybupropion/Bupropion
Ratio	Part A: Period 1 Treatment A	Part A: Period 2: Treatment D	Part A: Period 2: Treatment G
Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight (AUCt M/P) for 6-Hydroxybupropion/Bupropion	12.79 ± 40	10.92 ± 39	15.53 ± 47

SecondaryPart A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for 5-Hydroxyomeprazole/Omeprazole

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Geometric mean · Ratio

Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for 5-Hydroxyomeprazole/Omeprazole
Ratio	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for 5-Hydroxyomeprazole/Omeprazole	0.5417 ± 52	0.8096 ± 60

SecondaryPart A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for Hydroxymidazolam/Midazolam

Time frame:: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively
Reported as:: Geometric mean · Ratio

Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for Hydroxymidazolam/Midazolam
Ratio	Part A: Period 1: Treatment A	Part A: Period 2: Treatment E
Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for Hydroxymidazolam/Midazolam	0.4704 ± 43	0.3638 ± 26

SecondaryPart B: Tmax for Metformin

Time frame:: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Reported as:: Median · Hours

Part B: Tmax for Metformin
Hours	Part B: Period 1: Treatment A	Part B: Period 2: Treatment C
Part B: Tmax for Metformin	1.500 (1.00 to 5.00)	2.000 (1.50 to 4.00)

SecondaryPart B: Tmax for Furosemide

Time frame:: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Reported as:: Median · Hours

Part B: Tmax for Furosemide
Hours	Part B, Period 1: Treatment A	Part B: Period 2: Treatment C
Part B: Tmax for Furosemide	0.510 (0.50 to 1.00)	0.775 (0.50 to 1.50)

SecondaryPart B: Tmax for Rosuvastatin

Time frame:: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Reported as:: Median · Hours

Part B: Tmax for Rosuvastatin
Hours	Part B: Period 1: Treatment A	Part B: Period 2: Treatment C
Part B: Tmax for Rosuvastatin	5.000 (2.50 to 5.05)	2.500 (1.50 to 5.02)

SecondaryPart B: T½ for Metformin

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame:: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Reported as:: Mean · Hours

Part B: T½ for Metformin
Hours	Part B: Period 1: Treatment A	Part B: Period 2: Treatment C
Part B: T½ for Metformin	3.554 ± 0.9523	3.324 ± 0.8515

SecondaryPart B: T½ for Furosemide

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame:: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Reported as:: Mean · Hours

Part B: T½ for Furosemide
Hours	Part B: Period 1: Treatment A	Part B: Period 2: Treatment C
Part B: T½ for Furosemide	7.786 ± 5.1296	4.757 ± 2.1595

SecondaryPart B: T½ for Rosuvastatin

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Time frame:: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively
Reported as:: Mean · Hours

Part B: T½ for Rosuvastatin
Hours	Part B: Period 1: Treatment A	Part B: Period 2: Treatment C
Part B: T½ for Rosuvastatin	11.436 ± 8.9813	8.852 ± 3.1587

Other pre-specifiedPart A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not thought to be related to the investigational product. TEAE: any event that was not present before exposure to study drug (voxelotor or cocktail drugs \[probe substrates\]) or any event already present that worsened in either intensity or frequency after exposure to study drug. An SAE was defined as an AE that at any dose resulted in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or disability; a congenital anomaly/birth defect; other important medical events.

Time frame:: From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days)
Reported as:: Count of participants · Participants

Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Participants	Part A: Period 1	Part A: Period 2
TEAEs	4	9
SAEs	0	0

Other pre-specifiedPart B: Number of Participants With TEAEs and SAEs

An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not thought to be related to the investigational product. TEAE: any event that was not present before exposure to study drug (voxelotor or cocktail drugs \[probe substrates\]) or any event already present that worsened in either intensity or frequency after exposure to study drug. An SAE was defined as an AE that at any dose resulted in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or disability; a congenital anomaly/birth defect; other important medical events.

Time frame:: From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days)
Reported as:: Count of participants · Participants

Part B: Number of Participants With TEAEs and SAEs
Participants	Part B: Period 1	Part B: Period 2
TEAEs	1	2
SAEs	0	0

Other pre-specifiedPart A: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests

The following laboratory parameters were assessed: hematology: hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, red blood cell count, neutrophils, monocytes, lymphocytes, basophils and eosinophils. coagulation: prothrombin time, partial thromboplastin time, international normalized ratio. Serum Chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen, lactate dehydrogenase. Urinalysis: ketones, pH, protein, blood glucose, bilirubin, chloride, bicarbonate, phosphorous, potassium was assessed. Clinical significance of laboratory abnormalities was determined by investigator.

Time frame:: From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days)
Reported as:: Count of participants · Participants

Part A: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests
Participants	Part A: Period 1	Part A: Period 2
Part A: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests	0	0

Other pre-specifiedPart A: Number of Participants With Clinically Significant Abnormalities in Physical Examinations

A complete physical examination included cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight were also measured and recorded. Clinical significance of physical examinations was determined by investigator.

Time frame:: From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days)
Reported as:: Count of participants · Participants

Part A: Number of Participants With Clinically Significant Abnormalities in Physical Examinations
Participants	Part A: Period 1	Part A: Period 2
Part A: Number of Participants With Clinically Significant Abnormalities in Physical Examinations	1	0

Other pre-specifiedPart A: Number of Participants With Clinically Significant Abnormalities in Vital Signs

Vital signs included oral temperature, heart rate, respiratory rate (breaths per minute), and blood pressure. Blood pressure and heart rate were measured in a supine position using completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Clinical significance of vital signs was determined by investigator.

Time frame:: From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days)
Reported as:: Count of participants · Participants

Part A: Number of Participants With Clinically Significant Abnormalities in Vital Signs
Participants	Part A: Period 1	Part A: Period 2
Part A: Number of Participants With Clinically Significant Abnormalities in Vital Signs	0	1

Other pre-specifiedPart B: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests

Time frame:: From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days)
Reported as:: Count of participants · Participants

Part B: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests
Participants	Part B: Period 1	Part B: Period 2
Part B: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests	0	0

Other pre-specifiedPart B: Number of Participants With Clinically Significant Abnormalities in Physical Examinations

Time frame:: From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days)
Reported as:: Count of participants · Participants

Part B: Number of Participants With Clinically Significant Abnormalities in Physical Examinations
Participants	Part B: Period 1	Part B: Period 2
Part B: Number of Participants With Clinically Significant Abnormalities in Physical Examinations	0	0

Other pre-specifiedPart B: Number of Participants With Clinically Significant Abnormalities in Vital Signs

Time frame:: From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days)
Reported as:: Count of participants · Participants

Part B: Number of Participants With Clinically Significant Abnormalities in Vital Signs
Participants	Part B: Period 1	Part B: Period 2
Part B: Number of Participants With Clinically Significant Abnormalities in Vital Signs	0	0

Adverse events

Collected over Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days). Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Part A: Period 1	0/26 (0%)	0/26 (0%)	4/26 (15.4%)
Part A: Period 2	0/25 (0%)	0/25 (0%)	9/25 (36%)
Part B: Period 1	0/18 (0%)	0/18 (0%)	1/18 (5.6%)
Part B: Period 2	0/18 (0%)	0/18 (0%)	2/18 (11.1%)

Most frequent other events

Showing 10 of 13

Most frequent other events
Event	Part A: Period 1	Part A: Period 2	Part B: Period 1	Part B: Period 2
HeadacheNervous system disorders	0/26	7/25	1/18	2/18
Influenza like illnessGeneral disorders	0/26	2/25	0/18	0/18
Abdominal painGastrointestinal disorders	1/26	0/25	0/18	1/18
NauseaGastrointestinal disorders	0/26	0/25	1/18	0/18
Tooth abscessInfections and infestations	0/26	0/25	0/18	1/18
DizzinessNervous system disorders	0/26	1/25	0/18	0/18
ConstipationGastrointestinal disorders	0/26	1/25	0/18	0/18
DiarrhoeaGastrointestinal disorders	0/26	1/25	0/18	0/18
Muscle strainInjury, poisoning and procedural complications	1/26	1/25	0/18	0/18
COVID-19Infections and infestations	0/26	1/25	0/18	0/18

Baseline characteristics

Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]).

Age, Continuous
Age, Continuous(Years)	Part A:Treatment Sequence ABCDEFG	Part B: Treatment Sequence ABCD	Total
Mean	41.9 ± 8.89	36.9 ± 10.08	39.8 ± 9.61

Sex: Female, Male
Sex: Female, Male(Participants)	Part A:Treatment Sequence ABCDEFG	Part B: Treatment Sequence ABCD	Total
Female	9	5	14
Male	17	13	30

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Part A:Treatment Sequence ABCDEFG	Part B: Treatment Sequence ABCD	Total
Hispanic or Latino	6	8	14
Not Hispanic or Latino	20	10	30
Unknown or Not Reported	0	0	0

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Part A:Treatment Sequence ABCDEFG	Part B: Treatment Sequence ABCD	Total
American Indian or Alaska Native	0	0	0
Asian	1	1	2
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	9	7	16
White	16	10	26
More than one race	0	0	0
Unknown or Not Reported	0	0	0

Study locations

1 site

ICON Early Phase Services, LLC
San Antonio, Texas 78209, United States

References and documents

Study documents

Study protocol · Mar 2, 2023
Statistical analysis plan · Oct 10, 2023

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No — Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Nov 22, 2024, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT05981365
Lead sponsor: Pfizer
Responsible party: Sponsor
First posted: Aug 8, 2023
Start date: Apr 17, 2023
Primary completion: Oct 4, 2023
Completion: Oct 4, 2023
Results posted: Nov 22, 2024
Last update: Nov 22, 2024

Study contacts

Pfizer CT.gov Call Center

study director · Pfizer

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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