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CompletedNCT03258762Updated Mar 27, 2020Results posted

Phase I Study of Pyrimethamine in Healthy Japanese and Caucasian Subjects

A Phase 1 interventional study of Pyrimethamine and Calcium folinate in Toxoplasmosis, sponsored by GlaxoSmithKline. Completed at 1 site in Australia. Open to male participants aged 20 Years to 64 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2020-03-27.

Sponsored by GlaxoSmithKline · Phase 1, Interventional, and Treatment

Phase
Phase 1
Study type
Interventional
Enrollment
14
Allocation
Non-randomized
Ages
20 Years to 64 Years
Sex
Male
01

Study summary

Pyrimethamine in combination with a sulphonamide is known to be effective in the treatment of toxoplasmosis. However, Pyrimethamine has not been approved by the Japanese regulatory body (Pharmaceutical and Medical Devices Agency [PMDA]/ Ministry of Health, Labor and Welfare [MHLW]). The pharmacokinetics (PK) of Pyrimethamine has been investigated following administration of Sulfadoxine/Pyrimethamine tablet in healthy Japanese subjects. However, the study did not provide sufficient information for approval of Pyrimethamine in Japan; hence, PMDA has requested confirmation of the PK of Pyrimethamine in another PK study in Japanese and Caucasian healthy subjects. This study will be a single centre, open-label, parallel-group, single oral dose study to evaluate the PK, safety and tolerability of Pyrimethamine in healthy Japanese and Caucasian male subjects. Subjects will undergo a screening visit within 30 days prior to first dose of the study drug. On Day 1, subjects will be administered a single oral dose of pyrimethamine 50 milligrams (mg) along with calcium folinate 15 mg after an overnight fast of at least 10 hours. Subjects will continue to receive calcium folinate once daily until Day 8 of the treatment period. Blood sampling for PK analysis and safety assessments will be performed prior to dosing and over 22 days after dosing. Each subject will participate in the study for approximately 2 months from screening to follow-up.

02

Conditions studied

  • Toxoplasmosis

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Keywords

  • Japanese
  • Caucasian
  • pharmacokinetics
  • pyrimethamine
  • toxoplasmosis
03

Who can participate

Ages eligible
20 Years to 64 Years
Sexes eligible
Male
Accepts healthy volunteers
Yes

Inclusion criteria

  • Subjects should be between 20 and 64 years of age inclusive, at the time of signing the informed consent.
  • Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
  • Body weight >= 50 kilograms (kg) and body mass index (BMI) within the range 18.5 to 30.0 kilogram per square meters (kg/m\^2) (inclusive).
  • Japanese or Caucasian male.
  • A male subject must agree to use contraception during the treatment period and until follow-up.
  • Japanese ethnic origin defined as having been born in Japan, having four ethnic Japanese grandparents, holding a Japanese passport or identity papers and being able to speak Japanese. Subjects should also have lived outside Japan for less than 10 years at the time of screening.
  • Caucasian subject will be defined as an individual having four grandparents who are all descendants of the original people of Europe.
  • Capable of giving signed informed consent which includes compliance with the requirements and restrictions of the study.

Exclusion criteria

Exclusion Criteria:

  • Alanine aminotransferase (ALT) > 1.5 times upper limit of normal (ULN).
  • Bilirubin > 1.5 times ULN (isolated bilirubin > 1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \< 35 percent).
  • QT interval corrected for heart rate according to Fridericia's formula (QTcF) > 450 milliseconds (msec).
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • History of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data.
  • Abnormal blood pressure as determined by the investigator.
  • Hematological values: outside normal range at screening.
  • Serum creatinine level: outside normal range at screening visit.
  • Past or intended use of over-the-counter or prescription medication including herbal medications within 14 days prior to dosing.
  • Participation in the study would result in loss of blood or blood products in excess of 500 milliliters (mL) within 3 months.
  • Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
  • Current enrollment or past participation within the last 30 days before signing of consent in this clinical study involving an investigational study treatment or any other type of medical research.
  • Presence of Hepatitis B surface antigen (HBsAg) at screening or positive Hepatitis C antibody test result at screening. Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.
  • Positive Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study treatment. Test is optional and subjects with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing.
  • Positive pre-study drug/alcohol screen.
  • Positive human immunodeficiency virus (HIV) antibody test.
  • Regular use of known drugs of abuse.
  • Regular alcohol consumption within 6 months prior to the study defined as: For an average weekly intake of > 14 units for males. One unit is equivalent to 10 grams (g) of alcohol: a can of mid-strength (equivalent to 375 mL) beer, 1 glass (100 mL) of table wine or 1 measure (30 mL) of spirits (including rice wine).
  • History or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
  • Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.
04

Study design

Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
14 participants (actual)

Study arms

  • Experimental
    Healthy Japanese male subjects

    Healthy Japanese male subjects will receive a single oral dose of Pyrimethamine 50 mg in the fasted state co-administered with calcium folinate 15 mg on Day 1. Oral calcium folinate will be administered once daily until Day 8. Blood samples for PK analysis will be collected prior to administering first dose of Pyrimethamine and over 22 days post dose. Each subject will participate in the study for a duration of approximately 2 months from screening to follow-up.

    Drug: Pyrimethamine · Drug: Calcium folinate

  • Experimental
    Healthy Caucasian male subjects

    Healthy Caucasian male subjects will receive a single oral dose of Pyrimethamine 50 mg in the fasted state co-administered with calcium folinate 15 mg on Day 1. Oral calcium folinate will be administered once daily until Day 8. Blood samples for PK analysis will be collected prior to administering first dose of Pyrimethamine and over 22 days post dose. Each subject will participate in the study for a duration of approximately 2 months from screening to follow-up.

    Drug: Pyrimethamine · Drug: Calcium folinate

Interventions

  • DrugPyrimethamine

    Pyrimethamine will be available as 25 mg tablets. Subjects will be orally administered two pyrimethamine tablets on Day 1 in a fasted condition with 240 mL of water.

  • DrugCalcium folinate

    Calcium folinate will be available as 5 mg tablets. Subjects will be orally administered three calcium folinate tablets on Day 1 along with pyrimethamine followed by once daily administration of calcium folinate until Day 8. Each administration will be with 240 mL water.

05

What researchers measure

Primary outcomes

  1. Maximum Observed Concentration (Cmax) of Pyrimethamine in Healthy Japanese Male Participants

    Blood samples were collected at indicated time points. The Pharmacokinetic (PK) parameters were calculated by non-compartmental analysis. PK Population is defined as all participants who administered at least one dose of study treatment and who have PK sample taken and analyzed.

    Time frame: Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22

  2. Area Under the Concentration-time Curve From Time 0 to t (AUC[0-t]) of Pyrimethamine in Healthy Japanese Male Participants

    Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

    Time frame: Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22

  3. Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) of Pyrimethamine in Healthy Japanese Male Participants

    Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

    Time frame: Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22

  4. Area Under the Concentration-time Curve From Time 0 to 24 (AUC[0-24]) of Pyrimethamine in Healthy Japanese Male Participants

    Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

    Time frame: Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22

  5. Terminal Half-life (t1/2) of Pyrimethamine in Healthy Japanese Male Participants

    Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

    Time frame: Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22

  6. Time to Maximum Observed Concentration (Tmax) of Pyrimethamine in Healthy Japanese Male Participants

    Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

    Time frame: Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22

  7. Apparent Clearance Following Oral Dosing (CL/F) of Pyrimethamine in Healthy Japanese Male Participants

    Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

    Time frame: Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22

  8. Apparent Volume of Distribution Following Oral Dosing (Vd/F) of Pyrimethamine in Healthy Japanese Male Participants

    Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

    Time frame: Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22

Secondary outcomes

  1. Cmax of Pyrimethamine in Healthy Caucasian Male Participants

    Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

    Time frame: Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22

  2. AUC (0-t) of Pyrimethamine in Healthy Caucasian Male Participants

    Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

    Time frame: Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22

  3. AUC (0-inf) of Pyrimethamine in Healthy Caucasian Male Participants

    Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

    Time frame: Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22

  4. AUC (0-24) of Pyrimethamine in Healthy Caucasian Male Participants

    Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

    Time frame: Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22

  5. Tmax of Pyrimethamine in Healthy Caucasian Male Participants

    Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

    Time frame: Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22

  6. T1/2 of Pyrimethamine in Healthy Caucasian Male Participants

    Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

    Time frame: Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22

  7. CL/F of Pyrimethamine in Healthy Caucasian Male Participants

    Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

    Time frame: Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22

  8. Vd/F of Pyrimethamine in Healthy Caucasian Male Participants

    Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

    Time frame: Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22

  9. Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)

    An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or events associated with liver injury and impaired liver function were categorized as SAE. All participants who take at least one dose of study treatment were included in Safety Population.

    Time frame: Up to Day 23

  10. Change From Baseline of Clinical Chemistry Parameters: Glucose, Sodium, Calcium, Potassium, and Urea.

    Blood samples were collected for the analysis of clinical chemistry parameters including glucose, sodium, calcium, potassium, and urea at indicated time points. Day -1 value was defined as Baseline for clinical chemistry parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

    Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)

  11. Change From Baseline of Clinical Chemistry Parameters: Alkaline Phosphatase, Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST)

    Blood samples were collected for the analysis of clinical chemistry parameters including alkaline phosphatase, ALT and AST at indicated time points. Day -1 value was defined as Baseline for clinical chemistry parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

    Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)

  12. Change From Baseline of Clinical Chemistry Parameters: Direct Bilirubin, Bilirubin, Creatinine.

    Blood samples were collected for the analysis of clinical chemistry parameters including direct bilirubin, bilirubin and creatinine at indicated time points. Day -1 value was defined as Baseline for clinical chemistry parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

    Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)

  13. Change From Baseline of Clinical Chemistry Parameters: Protein

    Blood samples were collected for the analysis of clinical chemistry parameter including protein at indicated time points. Day -1 value was defined as Baseline for clinical chemistry parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

    Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)

  14. Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet and Leukocytes

    Blood samples were collected for the analysis of hematology parameters including basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelet and leukocytes at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value. Data was not available as all basophil values were below the detection limit. Hence, the change from baseline in basophil values were not calculated.

    Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)

  15. Change From Baseline in Hematology Parameter: Reticulocytes

    Blood samples were collected for the analysis of hematology parameter including reticulocytes at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

    Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)

  16. Change From Baseline in Hematology Parameter: Hematocrit

    Blood samples were collected for the analysis of hematology parameter including hematocrit at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

    Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)

  17. Change From Baseline in Hematology Parameter: Hemoglobin

    Blood samples were collected for the analysis of hematology parameter including hemoglobin at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

    Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)

  18. Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin

    Blood samples were collected for the analysis of hematology parameter including mean corpuscular hemoglobin at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

    Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)

  19. Change From Baseline in Hematology Parameter: Mean Corpuscular Volume

    Blood samples were collected for the analysis of hematology parameter including mean corpuscular volume at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

    Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)

  20. Change From Baseline in Hematology Parameter: Erythrocytes

    Blood samples were collected for the analysis of hematology parameter including erythrocytes at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

    Time frame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)

  21. Number of Participants With Abnormal Urinalysis Parameter

    The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters of can be read as Trace, + and ++ indicating proportional concentrations in the urine sample. Only participants with abnormal findings for urinalysis at any visit has been presented.

    Time frame: Day -1, 24, 96, 168, 336 and follow up (504 hours)

  22. Specific Gravity at Indicated Time Points

    Urine samples were collected for analysis of specific gravity of urine. Urinary specific gravity is a measure of the concentration of solutes in the urine. It measures the ratio of urine density compared with water density and provides information on the kidney's ability to concentrate urine.

    Time frame: Day -1, 24, 96, 168, 336 hours and follow up (504 hours)

  23. Urine Potential of Hydrogen (pH) at Indicated Time Points

    Urine samples were collected for analysis of urine pH. pH is calculated on a scale of 0 to 14, values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0).

    Time frame: Day -1, 24, 96, 168, 336 hours and follow up (504 hours)

  24. Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)

    Blood pressure of participants were measured at indicated time points in semi-supine position after 5 minutes rest. Day 1 (Pre-dose) value was defined as Baseline for vital sign parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

    Time frame: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours

  25. Change From Baseline in Pulse Rate

    Pulse rate of participants were measured at indicated time points in semi-supine position after 5 minutes rest. Day 1 (Pre-dose) value was defined as Baseline for vital sign parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

    Time frame: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours

  26. Change From Baseline in Temperature

    Temperature of participants were measured at indicated time points in semi-supine position after 5 minutes rest. Day 1 (Pre-dose) value was defined as Baseline for vital sign parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

    Time frame: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours

  27. Change From Baseline of Electrocardiogram (ECG) Parameters: PR Interval, QRS Duration, QT Interval, and QT Interval Corrected for Heart Rate by Fredericia's Formula (QTcF) Interval

    A single 12-lead ECG was obtained at indicated time points using an ECG machine that automatically measures PR, QRS, QT, and QTcF intervals. Day 1 (Pre-dose) value was defined as Baseline for ECG parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

    Time frame: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, and 504 hours

  28. Change From Baseline of ECG Parameter: ECG Mean Heart Rate

    A single 12-lead ECG was obtained at indicated time points using an ECG machine that automatically calculates mean ECG heart rate. Day 1 (Pre-dose) value was defined as Baseline for ECG parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

    Time frame: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, and 504 hours

06

Results

Posted Mar 27, 2019

Participant flow

This study was conducted in healthy Japanese and Caucasian male participants to evaluate safety, tolerability and pharmacokinetic (PK) parameters of Pyrimethamine. This study was conducted at a single center in Australia.

Participant flow — Overall Study
MilestoneHealthy Japanese ParticipantsHealthy Caucasian Participants
Started77
Completed76
Not completed01
Withdrew: Lost to follow-up01

Outcome measures

PrimaryMaximum Observed Concentration (Cmax) of Pyrimethamine in Healthy Japanese Male Participants

Blood samples were collected at indicated time points. The Pharmacokinetic (PK) parameters were calculated by non-compartmental analysis. PK Population is defined as all participants who administered at least one dose of study treatment and who have PK sample taken and analyzed.

Time frame:
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Reported as:
Geometric mean · Nanogram per milliliter
Maximum Observed Concentration (Cmax) of Pyrimethamine in Healthy Japanese Male Participants
Nanogram per milliliterHealthy Japanese Participants
Maximum Observed Concentration (Cmax) of Pyrimethamine in Healthy Japanese Male Participants430.5 ± 13.3
PrimaryArea Under the Concentration-time Curve From Time 0 to t (AUC[0-t]) of Pyrimethamine in Healthy Japanese Male Participants

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

Time frame:
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Reported as:
Geometric mean · Hours* nanogram per milliliter
Area Under the Concentration-time Curve From Time 0 to t (AUC[0-t]) of Pyrimethamine in Healthy Japanese Male Participants
Hours* nanogram per milliliterHealthy Japanese Participants
Area Under the Concentration-time Curve From Time 0 to t (AUC[0-t]) of Pyrimethamine in Healthy Japanese Male Participants59013.1 ± 15.3
PrimaryArea Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) of Pyrimethamine in Healthy Japanese Male Participants

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

Time frame:
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Reported as:
Geometric mean · Hours* nanogram per milliliter
Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) of Pyrimethamine in Healthy Japanese Male Participants
Hours* nanogram per milliliterHealthy Japanese Participants
Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) of Pyrimethamine in Healthy Japanese Male Participants64670.3 ± 16.6
PrimaryArea Under the Concentration-time Curve From Time 0 to 24 (AUC[0-24]) of Pyrimethamine in Healthy Japanese Male Participants

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

Time frame:
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Reported as:
Geometric mean · Hours* nanogram per milliliter
Area Under the Concentration-time Curve From Time 0 to 24 (AUC[0-24]) of Pyrimethamine in Healthy Japanese Male Participants
Hours* nanogram per milliliterHealthy Japanese Participants
Area Under the Concentration-time Curve From Time 0 to 24 (AUC[0-24]) of Pyrimethamine in Healthy Japanese Male Participants8756.3 ± 8.0
PrimaryTerminal Half-life (t1/2) of Pyrimethamine in Healthy Japanese Male Participants

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

Time frame:
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Reported as:
Geometric mean · Hours
Terminal Half-life (t1/2) of Pyrimethamine in Healthy Japanese Male Participants
HoursHealthy Japanese Participants
Terminal Half-life (t1/2) of Pyrimethamine in Healthy Japanese Male Participants122.75 ± 21.499
PrimaryTime to Maximum Observed Concentration (Tmax) of Pyrimethamine in Healthy Japanese Male Participants

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

Time frame:
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Reported as:
Median · Hours
Time to Maximum Observed Concentration (Tmax) of Pyrimethamine in Healthy Japanese Male Participants
HoursHealthy Japanese Participants
Time to Maximum Observed Concentration (Tmax) of Pyrimethamine in Healthy Japanese Male Participants2.000 (1.00 to 6.00)
PrimaryApparent Clearance Following Oral Dosing (CL/F) of Pyrimethamine in Healthy Japanese Male Participants

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

Time frame:
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Reported as:
Geometric mean · Milliliter per hour
Apparent Clearance Following Oral Dosing (CL/F) of Pyrimethamine in Healthy Japanese Male Participants
Milliliter per hourHealthy Japanese Participants
Apparent Clearance Following Oral Dosing (CL/F) of Pyrimethamine in Healthy Japanese Male Participants773.2 ± 16.6
PrimaryApparent Volume of Distribution Following Oral Dosing (Vd/F) of Pyrimethamine in Healthy Japanese Male Participants

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

Time frame:
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Reported as:
Geometric mean · Milliliter
Apparent Volume of Distribution Following Oral Dosing (Vd/F) of Pyrimethamine in Healthy Japanese Male Participants
MilliliterHealthy Japanese Participants
Apparent Volume of Distribution Following Oral Dosing (Vd/F) of Pyrimethamine in Healthy Japanese Male Participants135330.9 ± 5.5
SecondaryCmax of Pyrimethamine in Healthy Caucasian Male Participants

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

Time frame:
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Reported as:
Geometric mean · Nanogram per milliliter
Cmax of Pyrimethamine in Healthy Caucasian Male Participants
Nanogram per milliliterHealthy Caucasian Participants
Cmax of Pyrimethamine in Healthy Caucasian Male Participants371.1 ± 10.0
SecondaryAUC (0-t) of Pyrimethamine in Healthy Caucasian Male Participants

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

Time frame:
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Reported as:
Geometric mean · Hours* nanogram per milliliter
AUC (0-t) of Pyrimethamine in Healthy Caucasian Male Participants
Hours* nanogram per milliliterHealthy Caucasian Participants
AUC (0-t) of Pyrimethamine in Healthy Caucasian Male Participants41582.0 ± 26.9
SecondaryAUC (0-inf) of Pyrimethamine in Healthy Caucasian Male Participants

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

Time frame:
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Reported as:
Geometric mean · Hours* nanogram per milliliter
AUC (0-inf) of Pyrimethamine in Healthy Caucasian Male Participants
Hours* nanogram per milliliterHealthy Caucasian Participants
AUC (0-inf) of Pyrimethamine in Healthy Caucasian Male Participants44869.1 ± 27.0
SecondaryAUC (0-24) of Pyrimethamine in Healthy Caucasian Male Participants

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

Time frame:
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Reported as:
Geometric mean · Hours* nanogram per milliliter
AUC (0-24) of Pyrimethamine in Healthy Caucasian Male Participants
Hours* nanogram per milliliterHealthy Caucasian Participants
AUC (0-24) of Pyrimethamine in Healthy Caucasian Male Participants6930.8 ± 19.3
SecondaryTmax of Pyrimethamine in Healthy Caucasian Male Participants

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

Time frame:
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Reported as:
Median · Hours
Tmax of Pyrimethamine in Healthy Caucasian Male Participants
HoursHealthy Caucasian Participants
Tmax of Pyrimethamine in Healthy Caucasian Male Participants1.000 (1.000 to 6.00)
SecondaryT1/2 of Pyrimethamine in Healthy Caucasian Male Participants

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

Time frame:
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Reported as:
Mean · Hours
T1/2 of Pyrimethamine in Healthy Caucasian Male Participants
HoursHealthy Caucasian Participants
T1/2 of Pyrimethamine in Healthy Caucasian Male Participants99.46 ± 20.745
SecondaryCL/F of Pyrimethamine in Healthy Caucasian Male Participants

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

Time frame:
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Reported as:
Geometric mean · Milliliters per hour
CL/F of Pyrimethamine in Healthy Caucasian Male Participants
Milliliters per hourHealthy Caucasian Participants
CL/F of Pyrimethamine in Healthy Caucasian Male Participants1114.4 ± 27.0
SecondaryVd/F of Pyrimethamine in Healthy Caucasian Male Participants

Blood samples were collected at indicated time points. The PK parameters were calculated by non-compartmental analysis.

Time frame:
Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Reported as:
Geometric mean · Milliliters
Vd/F of Pyrimethamine in Healthy Caucasian Male Participants
MillilitersHealthy Caucasian Participants
Vd/F of Pyrimethamine in Healthy Caucasian Male Participants157125.8 ± 16.8
SecondaryNumber of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or events associated with liver injury and impaired liver function were categorized as SAE. All participants who take at least one dose of study treatment were included in Safety Population.

Time frame:
Up to Day 23
Reported as:
Count of participants · Participants
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
ParticipantsHealthy Japanese ParticipantsHealthy Caucasian Participants
Any AEs26
Any SAEs00
SecondaryChange From Baseline of Clinical Chemistry Parameters: Glucose, Sodium, Calcium, Potassium, and Urea.

Blood samples were collected for the analysis of clinical chemistry parameters including glucose, sodium, calcium, potassium, and urea at indicated time points. Day -1 value was defined as Baseline for clinical chemistry parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

Time frame:
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Reported as:
Mean · Millimoles per liter
Change From Baseline of Clinical Chemistry Parameters: Glucose, Sodium, Calcium, Potassium, and Urea.
Millimoles per literHealthy Japanese ParticipantsHealthy Caucasian Participants
Glucose, 24 hours, n=7, 7-0.33 ± 0.403-0.26 ± 0.310
Glucose, 96 hours, n=7, 7-0.43 ± 0.281-0.10 ± 0.200
Glucose, 168 hours, n=7, 7-0.60 ± 0.424-0.37 ± 0.214
Category title 4. : Glucose, 336 hours, n=7, 7-0.43 ± 0.335-0.09 ± 0.241
Glucose, Follow-up (504 hours), n= 7, 6-0.24 ± 0.3950.00 ± 0.276
Calcium, 24 hours, n=7, 7-0.116 ± 0.0608-0.054 ± 0.0862
Calcium, 96 hours, n=7, 7-0.006 ± 0.0947-0.033 ± 0.0670
Calcium, 168 hours, n=7, 7-0.006 ± 0.0730-0.033 ± 0.0739
Calcium, 336 hours, n=7, 7-0.083 ± 0.1224-0.040 ± 0.0432
Calcium, Follow up (504 hours), n=7, 6-0.100 ± 0.0781-0.042 ± 0.0637
Potassium, 24 hours, n=7, 7-0.03 ± 0.4270.00 ± 0.580
Potassium, 96 hours, n=7, 70.00 ± 0.356-0.11 ± 0.515
Potassium, 168 hours, n=7, 70.01 ± 0.463-0.21 ± 0.241
Potassium, 336 hours, n=7, 7-0.10 ± 0.216-0.21 ± 0.515
Potassium, Follow up (504 hours), n=7, 60.09 ± 0.402-0.22 ± 0.488
Sodium, 24 hours, n=7, 7-0.3 ± 3.550.0 ± 2.83
Sodium, 96 hours, n=7, 7-0.6 ± 3.051.0 ± 1.73
Sodium, 168 hours, n=7, 7-1.3 ± 2.631.7 ± 1.25
Sodium, 336 hours, n=7, 70.3 ± 1.38-0.3 ± 1.38
Sodium, Follow up (504 hours), n=7, 6-0.1 ± 1.86-0.5 ± 1.76
Urea, 24 hours, n=7, 70.33 ± 0.7721.01 ± 1.110
Urea, 96 hours, n=7, 70.26 ± 1.190-0.03 ± 0.660
Urea, 168 hours, n=7, 70.41 ± 1.053-0.26 ± 0.885
Urea, 336 hours, n=7, 7-0.16 ± 0.8961.06 ± 1.726
Urea, Follow up,(504 hours) n=7, 60.99 ± 1.9951.27 ± 1.317
SecondaryChange From Baseline of Clinical Chemistry Parameters: Alkaline Phosphatase, Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST)

Blood samples were collected for the analysis of clinical chemistry parameters including alkaline phosphatase, ALT and AST at indicated time points. Day -1 value was defined as Baseline for clinical chemistry parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

Time frame:
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Reported as:
Mean · International units per liter
Change From Baseline of Clinical Chemistry Parameters: Alkaline Phosphatase, Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST)
International units per literHealthy Japanese ParticipantsHealthy Caucasian Participants
Alkaline Phosphatase, 24 hours, n=7, 7-9.0 ± 11.60-3.3 ± 5.71
Alkaline Phosphatase, 96 hours, n=7, 7-6.7 ± 10.67-3.1 ± 2.97
Alkaline Phosphatase, 168 hours, n=7, 7-7.0 ± 11.56-4.1 ± 3.48
Alkaline Phosphatase, 336 hours, n=7, 7-11.0 ± 12.00-2.9 ± 5.90
Alkaline Phosphatase, Follow-up (504 hours), n=7,6-9.6 ± 11.18-9.3 ± 5.89
ALT, 24 hours, n=7, 7-3.0 ± 5.03-3.3 ± 2.81
ALT, 96 hours, n=7, 7-2.1 ± 6.23-5.1 ± 4.91
ALT, 168 hours, n=7, 70.7 ± 5.53-4.4 ± 8.16
ALT, 336 hours, n=7, 70.9 ± 9.84-3.9 ± 2.79
ALT, Follow up (504 hours), n=7, 60.4 ± 11.25-5.3 ± 4.59
AST, 24 hours, n=7, 7-3.4 ± 4.61-1.9 ± 4.56
AST, 96 hours, n=7, 7-3.7 ± 5.12-4.3 ± 6.55
AST, 168 hours, n=7, 7-2.0 ± 5.32-3.0 ± 7.62
AST, 336 hours, n=7, 70.3 ± 9.81-2.4 ± 5.86
AST, Follow up (504 hours), n=7, 60.0 ± 4.16-1.5 ± 6.83
SecondaryChange From Baseline of Clinical Chemistry Parameters: Direct Bilirubin, Bilirubin, Creatinine.

Blood samples were collected for the analysis of clinical chemistry parameters including direct bilirubin, bilirubin and creatinine at indicated time points. Day -1 value was defined as Baseline for clinical chemistry parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

Time frame:
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Reported as:
Mean · Micromoles per liter
Change From Baseline of Clinical Chemistry Parameters: Direct Bilirubin, Bilirubin, Creatinine.
Micromoles per literHealthy Japanese ParticipantsHealthy Caucasian Participants
Direct bilirubin, 24 hours, n=7, 70.7 ± 1.980.6 ± 0.53
Direct bilirubin, 96 hours, n=7, 70.4 ± 1.270.7 ± 1.70
Direct bilirubin, 168 hours, n=7, 70.6 ± 2.300.9 ± 1.35
Direct bilirubin, 336 hours, n=7, 7-0.3 ± 1.600.9 ± 1.95
Direct bilirubin, Follow-up (504 hours), n=7, 6-0.3 ± 1.500.3 ± 1.97
Bilirubin, 24 hours, n=7, 71.4 ± 5.163.1 ± 4.56
Bilirubin, 96 hours, n=7, 7-0.6 ± 5.832.4 ± 5.47
Bilirubin, 168 hours, n=7, 70.7 ± 8.101.0 ± 5.23
Bilirubin, 336 hours, n=7, 7-4.0 ± 5.83-0.3 ± 5.22
Bilirubin, Follow up (504 hours), n=7, 6-3.4 ± 5.56-1.7 ± 7.06
Creatinine, 24 hours, n=7, 721.7 ± 8.1626.6 ± 6.68
Creatinine, 96 hours, n=7, 724.4 ± 5.0630.1 ± 7.84
Creatinine, 168 hours, n=7, 720.9 ± 5.0824.6 ± 4.83
Creatinine, 336 hours, n=7, 714.1 ± 6.1814.9 ± 4.71
Creatinine, Follow up (504 hours), n=7, 65.6 ± 6.169.5 ± 7.77
SecondaryChange From Baseline of Clinical Chemistry Parameters: Protein

Blood samples were collected for the analysis of clinical chemistry parameter including protein at indicated time points. Day -1 value was defined as Baseline for clinical chemistry parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

Time frame:
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Reported as:
Mean · Gram per liter
Change From Baseline of Clinical Chemistry Parameters: Protein
Gram per literHealthy Japanese ParticipantsHealthy Caucasian Participants
24 hours, n=7, 7-4.9 ± 4.06-2.3 ± 4.03
96 hours, n=7, 7-4.6 ± 6.80-2.9 ± 1.95
168 hours, n=7, 7-3.6 ± 7.32-4.1 ± 2.67
336 hours, n=7, 7-4.4 ± 6.29-2.4 ± 1.99
Follow-up (504 hours), n=7, 6-5.4 ± 4.69-4.2 ± 3.54
SecondaryChange From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet and Leukocytes

Blood samples were collected for the analysis of hematology parameters including basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelet and leukocytes at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value. Data was not available as all basophil values were below the detection limit. Hence, the change from baseline in basophil values were not calculated.

Time frame:
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Reported as:
Mean · 10^9 cells per liter
Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet and Leukocytes
10^9 cells per literHealthy Japanese ParticipantsHealthy Caucasian Participants
Eosinophils, 24 hours, n=4, 3-0.03 ± 0.0960.07 ± 0.058
Eosinophils, 96 hours, n=4, 3-0.03 ± 0.1500.00 ± 0.100
Eosinophils, 168 hours, n=4, 30.00 ± 0.1150.00 ± 0.100
Eosinophils, 336 hours, n=3, 30.00 ± 0.1000.00 ± 0.100
Eosinophils, Follow up (504 hours), n=4, 2-0.05 ± 0.058-0.05 ± 0.071
Lymphocytes, 24 hours, n=7, 7-0.27 ± 0.5280.36 ± 0.251
Lymphocytes, 96 hours, n=7, 7-0.11 ± 0.5080.30 ± 0.277
Lymphocytes, 168 hours, n=7, 7-0.10 ± 0.5740.26 ± 0.276
Lymphocytes, 336 hours, n=7, 7-0.50 ± 0.6160.09 ± 0.363
Lymphocytes, Follow up (504 hours), n=7, 6-0.41 ± 0.4410.00 ± 0.514
Monocytes, 24 hours, n=7, 7-0.11 ± 0.1070.04 ± 0.113
Monocytes, 96 hours, n=7, 7-0.04 ± 0.190-0.01 ± 0.227
Monocytes, 168 hours, n=7, 70.01 ± 0.1860.00 ± 0.153
Monocytes, 336 hours, n=7, 7-0.09 ± 0.1770.00 ± 0.115
Monocytes, Follow up (504 hours), n=7, 6-0.06 ± 0.172-0.03 ± 0.216
Neutrophils, 24 hours, n=7, 7-0.63 ± 0.939-0.54 ± 0.702
Neutrophils, 96 hours, n=7, 7-0.76 ± 1.066-0.79 ± 0.799
Neutrophils, 168 hours, n=7, 7-0.61 ± 1.128-0.69 ± 0.546
Neutrophils, 336 hours, n=7, 7-0.93 ± 1.181-0.96 ± 0.516
Neutrophils, Follow up (504 hours), n=7, 6-1.09 ± 1.299-0.97 ± 0.612
Platelet, 24 hours, n=7, 7-18.3 ± 18.82-11.6 ± 27.99
Platelet, 96 hours, n=7, 7-15.1 ± 20.82-6.3 ± 22.65
Platelet, 168 hours, n=7, 7-20.0 ± 26.58-13.3 ± 38.84
Platelet, 336 hours, n=7, 7-22.4 ± 35.09-27.3 ± 38.70
Platelet, Follow up (504 hours), n=7, 6-22.9 ± 31.49-24.3 ± 44.96
Leukocytes, 24 hours, n=7, 7-1.00 ± 1.441-0.09 ± 0.912
Leukocytes, 96 hours, n=7, 7-0.89 ± 1.624-0.46 ± 1.149
Leukocytes, 168 hours, n=7, 7-0.67 ± 1.738-0.36 ± 0.735
Leukocytes, 336 hours, n=7, 7-1.50 ± 1.649-0.77 ± 0.911
Leukocytes, Follow up (504 hours), n=7, 6-1.59 ± 1.757-0.97 ± 1.159
SecondaryChange From Baseline in Hematology Parameter: Reticulocytes

Blood samples were collected for the analysis of hematology parameter including reticulocytes at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

Time frame:
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Reported as:
Mean · Proportion of reticulocytes in blood
Change From Baseline in Hematology Parameter: Reticulocytes
Proportion of reticulocytes in bloodHealthy Japanese ParticipantsHealthy Caucasian Participants
24 hours, n= 7, 7-0.0016 ± 0.001720.0003 ± 0.00125
96 hours, n=7, 70.0017 ± 0.00544-0.0006 ± 0.00162
168 hours, n=7, 70.0013 ± 0.005770.0009 ± 0.00212
336 hours, n= 7, 7-0.0011 ± 0.004300.0003 ± 0.00335
Follow up (504 hours), n=7, 6-0.0013 ± 0.003680.0017 ± 0.00308
SecondaryChange From Baseline in Hematology Parameter: Hematocrit

Blood samples were collected for the analysis of hematology parameter including hematocrit at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

Time frame:
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Reported as:
Mean · Proportion of red blood cells in blood
Change From Baseline in Hematology Parameter: Hematocrit
Proportion of red blood cells in bloodHealthy Japanese ParticipantsHealthy Caucasian Participants
24 hours, n= 7, 70.001 ± 0.01350.007 ± 0.0198
96 hours, n=7, 70.009 ± 0.0186-0.006 ± 0.0127
168 hours, n=7, 7-0.004 ± 0.0181-0.006 ± 0.0162
336 hours, n= 7, 7-0.014 ± 0.0190-0.016 ± 0.0215
Follow up (504 hours), n=7, 6-0.036 ± 0.0230-0.025 ± 0.0152
SecondaryChange From Baseline in Hematology Parameter: Hemoglobin

Blood samples were collected for the analysis of hematology parameter including hemoglobin at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

Time frame:
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Reported as:
Mean · Gram per liter
Change From Baseline in Hematology Parameter: Hemoglobin
Gram per literHealthy Japanese ParticipantsHealthy Caucasian Participants
24 hours, n= 7, 72.0 ± 2.453.0 ± 5.23
96 hours, n=7, 72.6 ± 5.710.0 ± 2.24
168 hours, n=7, 70.0 ± 5.32-1.7 ± 5.50
336 hours, n= 7, 7-4.9 ± 4.95-3.6 ± 4.54
Follow up (504 hours), n=7, 6-12.1 ± 6.47-6.0 ± 3.22
SecondaryChange From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin

Blood samples were collected for the analysis of hematology parameter including mean corpuscular hemoglobin at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

Time frame:
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Reported as:
Mean · Picogram
Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin
PicogramHealthy Japanese ParticipantsHealthy Caucasian Participants
24 hours, n= 7, 70.0 ± 0.000.0 ± 0.00
96 hours, n=7, 7-0.4 ± 0.530.0 ± 0.58
168 hours, n=7, 70.0 ± 0.82-0.1 ± 0.69
336 hours, n= 7, 70.1 ± 0.90-0.3 ± 0.76
Follow up (504 hours), n=7, 60.0 ± 0.58-0.2 ± 0.41
SecondaryChange From Baseline in Hematology Parameter: Mean Corpuscular Volume

Blood samples were collected for the analysis of hematology parameter including mean corpuscular volume at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

Time frame:
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Reported as:
Mean · Femtoliter
Change From Baseline in Hematology Parameter: Mean Corpuscular Volume
FemtoliterHealthy Japanese ParticipantsHealthy Caucasian Participants
24 hours, n= 7, 7-0.6 ± 0.98-0.7 ± 2.43
96 hours, n=7, 70.1 ± 0.90-1.4 ± 1.40
168 hours, n=7, 7-0.3 ± 1.11-1.1 ± 1.35
336 hours, n= 7, 70.4 ± 0.98-1.9 ± 1.68
Follow up (504 hours), n=7, 60.4 ± 1.27-1.7 ± 1.21
SecondaryChange From Baseline in Hematology Parameter: Erythrocytes

Blood samples were collected for the analysis of hematology parameter including erythrocytes at indicated time points. Day -1 value was defined as Baseline for hematology parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

Time frame:
Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
Reported as:
Mean · 10^12 cells per liter
Change From Baseline in Hematology Parameter: Erythrocytes
10^12 cells per literHealthy Japanese ParticipantsHealthy Caucasian Participants
24 hours, n= 7, 70.026 ± 0.08200.100 ± 0.1943
96 hours, n=7, 70.101 ± 0.16420.006 ± 0.0680
168 hours, n=7, 7-0.024 ± 0.2204-0.021 ± 0.1906
336 hours, n= 7, 7-0.187 ± 0.2051-0.079 ± 0.1901
Follow up (504 hours), n=7, 6-0.411 ± 0.2032-0.183 ± 0.1229
SecondaryNumber of Participants With Abnormal Urinalysis Parameter

The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters of can be read as Trace, + and ++ indicating proportional concentrations in the urine sample. Only participants with abnormal findings for urinalysis at any visit has been presented.

Time frame:
Day -1, 24, 96, 168, 336 and follow up (504 hours)
Reported as:
Count of participants · Participants
Number of Participants With Abnormal Urinalysis Parameter
ParticipantsHealthy Japanese ParticipantsHealthy Caucasian Participants
Ketones, 336 hours, ++20
Ketones, 336 hours, trace01
Ketones, follow up (504 hours), +10
Occult blood, 336 hours, +10
Occult blood, follow up, trace01
Protein, Day -1, trace01
Protein, 24 hours, trace23
Protein, 96 hours, trace24
Protein, 168 hours, trace21
Protein, 336 hours, trace33
SecondarySpecific Gravity at Indicated Time Points

Urine samples were collected for analysis of specific gravity of urine. Urinary specific gravity is a measure of the concentration of solutes in the urine. It measures the ratio of urine density compared with water density and provides information on the kidney's ability to concentrate urine.

Time frame:
Day -1, 24, 96, 168, 336 hours and follow up (504 hours)
Reported as:
Mean · Ratio
Specific Gravity at Indicated Time Points
RatioHealthy Japanese ParticipantsHealthy Caucasian Participants
Day -1, n=7, 71.0127 ± 0.008561.0177 ± 0.00720
24 hours, n=7, 71.0214 ± 0.006211.0256 ± 0.00665
96 hours, n=7, 71.0211 ± 0.008321.0236 ± 0.00550
168 hours, n=7, 71.0211 ± 0.008211.0207 ± 0.00562
336 hours, n=7, 71.0193 ± 0.008711.0246 ± 0.00945
Follow up (504 hours), n=7, 61.0183 ± 0.007201.0222 ± 0.00728
SecondaryUrine Potential of Hydrogen (pH) at Indicated Time Points

Urine samples were collected for analysis of urine pH. pH is calculated on a scale of 0 to 14, values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0).

Time frame:
Day -1, 24, 96, 168, 336 hours and follow up (504 hours)
Reported as:
Mean · pH
Urine Potential of Hydrogen (pH) at Indicated Time Points
pHHealthy Japanese ParticipantsHealthy Caucasian Participants
Day -1, n=7, 76.21 ± 0.6996.86 ± 1.144
24 hours, n=7, 75.86 ± 0.2445.79 ± 0.567
96 hours, n=7, 75.79 ± 0.3936.07 ± 0.345
168 hours, n=7, 75.93 ± 0.5356.07 ± 0.450
336 hours, n=7, 76.00 ± 0.5776.00 ± 0.408
Follow up (504 hours), n=7, 66.43 ± 0.6736.08 ± 0.492
SecondaryChange From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)

Blood pressure of participants were measured at indicated time points in semi-supine position after 5 minutes rest. Day 1 (Pre-dose) value was defined as Baseline for vital sign parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

Time frame:
Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours
Reported as:
Mean · Millimeter of mercury (mmHg)
Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
Millimeter of mercury (mmHg)Healthy Japanese ParticipantsHealthy Caucasian Participants
DBP, 4 hours, n=7, 7-7.0 ± 6.98-0.7 ± 6.92
DBP, 12 hours, n=7, 7-5.4 ± 6.02-0.3 ± 8.60
DBP, 24 hours, n=7, 7-3.9 ± 5.24-2.9 ± 4.74
DBP, 48 hours, n=7, 7-3.4 ± 6.502.0 ± 2.08
DBP, 72 hours, n=7, 7-4.0 ± 9.11-4.6 ± 5.13
DBP, 96 hours, n=7, 7-5.9 ± 10.14-2.7 ± 9.29
DBP, 120 hours, n=7, 7-4.1 ± 10.02-3.4 ± 11.16
DBP, 144 hours, n=7, 7-7.6 ± 8.81-5.4 ± 7.32
DBP, 168 hours, n=7, 7-5.1 ± 10.25-1.0 ± 6.68
DBP, 336 hours, n=7, 7-5.7 ± 9.66-5.3 ± 4.39
DBP, 504 hours, n=7, 6-7.3 ± 8.73-0.7 ± 10.01
SBP, 4 hours, n=7, 7-0.1 ± 5.931.3 ± 7.04
SBP, 12 hours, n=7, 71.4 ± 3.411.0 ± 9.73
SBP, 24 hours, n=7, 7-1.0 ± 6.32-3.4 ± 11.03
SBP, 48 hours, n=7, 7-1.9 ± 6.20-1.1 ± 8.55
SBP, 72 hours, n=7, 7-1.0 ± 6.78-4.6 ± 11.80
SBP, 96 hours, n=7, 7-1.4 ± 9.962.6 ± 8.48
SBP, 120 hours, n=7, 7-6.3 ± 5.530.9 ± 7.88
SBP,144 hours, n=7, 7-6.6 ± 7.30-3.3 ± 6.52
SBP, 168 hours, n=7, 70.4 ± 8.180.9 ± 6.67
SBP, 336 hours, n=7, 7-3.9 ± 11.05-2.6 ± 8.81
SBP, 504 hours, n=7, 6-5.0 ± 7.92-1.5 ± 5.89
SecondaryChange From Baseline in Pulse Rate

Pulse rate of participants were measured at indicated time points in semi-supine position after 5 minutes rest. Day 1 (Pre-dose) value was defined as Baseline for vital sign parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

Time frame:
Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours
Reported as:
Mean · Beats per minute
Change From Baseline in Pulse Rate
Beats per minuteHealthy Japanese ParticipantsHealthy Caucasian Participants
4 hours, n=7, 73.6 ± 5.194.7 ± 6.95
12 hours, n=7, 75.0 ± 11.4510.1 ± 6.74
24 hours, n=7, 73.4 ± 8.38-5.0 ± 4.36
48 hours, n=7, 73.4 ± 18.12-0.3 ± 4.39
72 hours, n=7, 74.9 ± 11.26-0.3 ± 4.15
96 hours, n=7, 71.4 ± 13.440.6 ± 3.21
120 hours, n=7, 71.1 ± 9.582.0 ± 6.11
144 hours, n=7, 70.1 ± 16.74-0.1 ± 3.24
168 hours, n=7, 74.4 ± 17.627.1 ± 7.20
336 hours, n=7, 71.0 ± 17.611.6 ± 7.50
504 hours, n=7, 6-2.1 ± 18.522.2 ± 6.79
SecondaryChange From Baseline in Temperature

Temperature of participants were measured at indicated time points in semi-supine position after 5 minutes rest. Day 1 (Pre-dose) value was defined as Baseline for vital sign parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

Time frame:
Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours
Reported as:
Mean · Celsius
Change From Baseline in Temperature
CelsiusHealthy Japanese ParticipantsHealthy Caucasian Participants
4 hours, n=7, 7-0.01 ± 0.1950.27 ± 0.095
12 hours, n=7, 70.04 ± 0.1720.26 ± 0.230
24 hours, n=7, 7-0.07 ± 0.150-0.01 ± 0.241
48 hours, n=7, 7-0.16 ± 0.190-0.04 ± 0.113
72 hours, n=7, 7-0.10 ± 0.271-0.10 ± 0.100
96 hours, n=7, 7-0.11 ± 0.212-0.04 ± 0.098
120 hours, n=7, 7-0.10 ± 0.191-0.17 ± 0.189
144 hours, n=7, 7-0.14 ± 0.223-0.09 ± 0.107
168 hours, n=7, 7-0.09 ± 0.1860.01 ± 0.135
336 hours, n=7, 7-0.27 ± 0.315-0.13 ± 0.170
504 hours, n=7, 6-0.26 ± 0.479-0.07 ± 0.242
SecondaryChange From Baseline of Electrocardiogram (ECG) Parameters: PR Interval, QRS Duration, QT Interval, and QT Interval Corrected for Heart Rate by Fredericia's Formula (QTcF) Interval

A single 12-lead ECG was obtained at indicated time points using an ECG machine that automatically measures PR, QRS, QT, and QTcF intervals. Day 1 (Pre-dose) value was defined as Baseline for ECG parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

Time frame:
Baseline (Pre-dose on Day 1), 4, 12, 24, 48, and 504 hours
Reported as:
Mean · Millisecond
Change From Baseline of Electrocardiogram (ECG) Parameters: PR Interval, QRS Duration, QT Interval, and QT Interval Corrected for Heart Rate by Fredericia's Formula (QTcF) Interval
MillisecondHealthy Japanese ParticipantsHealthy Caucasian Participants
PR Interval, 4 hours, n=7, 7-5.3 ± 4.07-4.6 ± 5.44
PR Interval, 12 hours, n=7, 7-8.7 ± 10.52-5.9 ± 3.89
PR Interval, 24 hours, n=7, 7-3.1 ± 8.67-0.1 ± 5.70
PR Interval, 48 hours, n=7, 7-17.0 ± 33.800.3 ± 5.41
PR Interval, 504 hours, n=7, 6-7.3 ± 10.052.2 ± 9.91
QRS duration, 4 hours, n=7, 7-1.6 ± 1.40-2.1 ± 3.24
QRS duration, 12 hours, n=7, 7-0.3 ± 3.86-0.6 ± 4.04
QRS duration, 24 hours, n=7, 70.3 ± 2.50-2.0 ± 3.96
QRS duration, 48 hours, n=7, 73.1 ± 11.160.4 ± 7.91
QRS duration, 504 hours, n=7, 6-0.3 ± 3.59-0.8 ± 8.08
QT interval, 4 hours, n=7, 7-4.0 ± 15.59-20.4 ± 14.28
QT interval, 12 hours, n=7, 7-17.9 ± 29.17-21.7 ± 20.09
QT interval, 24 hours, n=7, 74.3 ± 25.79-7.3 ± 7.48
QT interval, 48 hours, n=7, 72.3 ± 21.55-14.7 ± 13.50
QT interval, 504 hours, n=7, 614.7 ± 32.07-9.2 ± 22.93
QTcF interval, 4 hours, n=7, 7-4.9 ± 10.42-6.6 ± 12.39
QTcF interval, 12 hours, n=7, 7-7.7 ± 8.94-5.7 ± 12.72
QTcF interval, 24 hours, n=7, 7-0.9 ± 7.71-0.1 ± 12.76
QTcF interval, 48 hours, n=7, 711.6 ± 40.64-2.9 ± 12.88
QTcF interval, 504 hours, n=7, 66.7 ± 12.84-2.2 ± 9.64
SecondaryChange From Baseline of ECG Parameter: ECG Mean Heart Rate

A single 12-lead ECG was obtained at indicated time points using an ECG machine that automatically calculates mean ECG heart rate. Day 1 (Pre-dose) value was defined as Baseline for ECG parameters. Change from Baseline was defined as difference between post-dose visit values minus Baseline value.

Time frame:
Baseline (Pre-dose on Day 1), 4, 12, 24, 48, and 504 hours
Reported as:
Mean · Beats per minute
Change From Baseline of ECG Parameter: ECG Mean Heart Rate
Beats per minuteHealthy Japanese ParticipantsHealthy Caucasian Participants
4 hours, n=7, 7-2.3 ± 11.376.0 ± 6.32
12 hours, n=7, 72.3 ± 19.917.1 ± 5.37
24 hours, n=7, 7-5.3 ± 19.673.1 ± 6.72
48 hours, n=7, 76.7 ± 15.645.0 ± 5.32
504 hours, n=7, 6-7.1 ± 25.713.2 ± 7.65

Adverse events

Collected over Serious adverse events (SAEs) and non-serious AEs were collected up to Day 23. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Healthy Japanese Participants0/7 (0%)0/7 (0%)2/7 (28.6%)
Healthy Caucasian Participants0/7 (0%)0/7 (0%)6/7 (85.7%)
Most frequent other events
Most frequent other events
EventHealthy Japanese ParticipantsHealthy Caucasian Participants
FolliculitisInfections and infestations0/71/7
Upper respiratory tract infectionInfections and infestations0/71/7
Viral infectionInfections and infestations1/70/7
Abdominal discomfortGastrointestinal disorders0/71/7
NauseaGastrointestinal disorders0/71/7
HeadacheNervous system disorders0/71/7
Tension headacheNervous system disorders1/70/7
Catheter site painGeneral disorders0/71/7
Musculoskeletal painMusculoskeletal and connective tissue disorders0/71/7
Dry skinSkin and subcutaneous tissue disorders1/70/7

Baseline characteristics

Age, Continuous
Age, Continuous(Years)Healthy Japanese ParticipantsHealthy Caucasian ParticipantsTotal
Mean29.0 ± 3.2730.7 ± 6.0229.9 ± 4.74
Sex: Female, Male
Sex: Female, Male(Participants)Healthy Japanese ParticipantsHealthy Caucasian ParticipantsTotal
Female000
Male7714
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Healthy Japanese ParticipantsHealthy Caucasian ParticipantsTotal
Asian: Japanese Heritage/East Asian707
White/Caucasian/European heritage077
07

Study locations

1 site
  • GSK Investigational Site
    Melbourne, Victoria 3004, Australia
08

References and documents

Publications

  • Iida T, Nand RA, Ino H, Ogura H, Itoh H, Igarashi H, Numachi Y, Gross AS. Evaluation of the Pharmacokinetics, Safety, and Tolerability of a Single Oral Dose of Pyrimethamine in Healthy Male Subjects of Japanese and European Ancestry. Clin Pharmacol Drug Dev. 2020 Aug;9(6):768-773. doi: 10.1002/cpdd.771. Epub 2020 Jan 16. PubMed 31950646 ↗

Study documents

  • Study protocol · Jul 19, 2017
  • Statistical analysis plan · Sep 15, 2017

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

Individual participant data

Plan to share: Yes — IPD for this study will be made available via the Clinical Study Data Request site.

Supporting information: Study protocol, Sap, Icf, Csr

09

Registry details

Key details

Study ID
NCT03258762
Lead sponsor
GlaxoSmithKline
Responsible party
Sponsor
First posted
Aug 23, 2017
Start date
Sep 25, 2017
Primary completion
Nov 19, 2017
Completion
Nov 19, 2017
Results posted
Mar 27, 2019
Last update
Mar 27, 2020

Study contacts

GSK Clinical Trials
study director · GlaxoSmithKline

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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