Phase I Study of Pyrimethamine in Healthy Japanese and Caucasian Subjects

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03258762
• Collaborator: (none)
• Enrollment: 14
• Location: 1
• Arms: 2
• Actual Duration (Months): 1.8
• Patients Per Site Per Month: 7.7

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Toxoplasmosis	Drug: Pyrimethamine; Drug: Calcium folinate	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single Centre, Open-label, Parallel-group, Single Oral Dose Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Pyrimethamine in Healthy Japanese and Caucasian Male Subjects
• Actual Study Start Date: Sep 25, 2017
• Actual Primary Completion Date: Nov 19, 2017
• Actual Study Completion Date: Nov 19, 2017

Arms and Interventions

Arm	Intervention/Treatment
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; 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.; Drug: Calcium 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.
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; 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.; Drug: Calcium 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.

Outcome Measures

Primary Outcome Measures

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

   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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Secondary Outcome Measures

1. Cmax of Pyrimethamine in Healthy Caucasian Male Participants [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]

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

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

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

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

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

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

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

5. Tmax of Pyrimethamine in Healthy Caucasian Male Participants [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]

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

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

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

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

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

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

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

9. Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) [Up to Day 23]

   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.

10. Change From Baseline of Clinical Chemistry Parameters: Glucose, Sodium, Calcium, Potassium, and Urea. [Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)]

    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.

11. Change From Baseline of Clinical Chemistry Parameters: Alkaline Phosphatase, Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST) [Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)]

    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.

12. Change From Baseline of Clinical Chemistry Parameters: Direct Bilirubin, Bilirubin, Creatinine. [Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)]

    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.

13. Change From Baseline of Clinical Chemistry Parameters: Protein [Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)]

    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.

14. Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet and Leukocytes [Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)]

    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.

15. Change From Baseline in Hematology Parameter: Reticulocytes [Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)]

    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.

16. Change From Baseline in Hematology Parameter: Hematocrit [Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)]

    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.

17. Change From Baseline in Hematology Parameter: Hemoglobin [Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)]

    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.

18. Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin [Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)]

    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.

19. Change From Baseline in Hematology Parameter: Mean Corpuscular Volume [Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)]

    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.

20. Change From Baseline in Hematology Parameter: Erythrocytes [Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)]

    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.

21. Number of Participants With Abnormal Urinalysis Parameter [Day -1, 24, 96, 168, 336 and follow up (504 hours)]

    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.

22. Specific Gravity at Indicated Time Points [Day -1, 24, 96, 168, 336 hours and follow up (504 hours)]

    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.

23. Urine Potential of Hydrogen (pH) at Indicated Time Points [Day -1, 24, 96, 168, 336 hours and follow up (504 hours)]

    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).

24. Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) [Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours]

    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.

25. Change From Baseline in Pulse Rate [Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours]

    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.

26. Change From Baseline in Temperature [Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours]

    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.

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 [Baseline (Pre-dose on Day 1), 4, 12, 24, 48, and 504 hours]

    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.

28. Change From Baseline of ECG Parameter: ECG Mean Heart Rate [Baseline (Pre-dose on Day 1), 4, 12, 24, 48, and 504 hours]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 64 Years
• Sexes Eligible for Study: 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:

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Melbourne	Victoria	Australia	3004

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

• Study Protocol - Jul 19, 2017
• Statistical Analysis Plan - Sep 15, 2017

More Information

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.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT03258762
• Other Study ID Numbers: 204678
• First Posted: Aug 23, 2017
• Last Update Posted: Mar 27, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by GlaxoSmithKline: Japanese; Caucasian; pharmacokinetics; pyrimethamine; toxoplasmosis
• Additional relevant MeSH terms: Toxoplasmosis; Leucovorin; Pyrimethamine; Calcium; Levoleucovorin

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	A total of 14 healthy participants were enrolled in this study.

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 milligram (mg) tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 milliliters (mL) of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Period Title: Overall Study
STARTED	7	7
COMPLETED	7	6
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants	Total
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Total of all reporting groups
Overall Participants	7	7	14
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	29.0 (3.27)	30.7 (6.02)	29.9 (4.74)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	7 100%	7 100%	14 100%
Race/Ethnicity, Customized (Number) [Number]
Asian: Japanese Heritage/East Asian	7 100%	0 0%	7 50%
White/Caucasian/European heritage	0 0%	7 100%	7 50%

Outcome Measures

1. Primary Outcome

Title	Maximum Observed Concentration (Cmax) of Pyrimethamine in Healthy Japanese Male Participants
Description	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	Healthy Japanese Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7
Geometric Mean (Geometric Coefficient of Variation) [Nanogram per milliliter]	430.5 (13.3)

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	Healthy Japanese Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7
Geometric Mean (Geometric Coefficient of Variation) [Hours* nanogram per milliliter]	59013.1 (15.3)

3. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	Healthy Japanese Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7
Geometric Mean (Geometric Coefficient of Variation) [Hours* nanogram per milliliter]	64670.3 (16.6)

4. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	Healthy Japanese Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7
Geometric Mean (Geometric Coefficient of Variation) [Hours* nanogram per milliliter]	8756.3 (8.0)

5. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	Healthy Japanese Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7
Geometric Mean (Geometric Coefficient of Variation) [Hours]	122.75 (21.499)

6. Primary Outcome

Title	Time to Maximum Observed Concentration (Tmax) of Pyrimethamine in Healthy Japanese Male Participants
Description	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	Healthy Japanese Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7
Median (Full Range) [Hours]	2.000

7. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	Healthy Japanese Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7
Geometric Mean (Geometric Coefficient of Variation) [Milliliter per hour]	773.2 (16.6)

8. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	Healthy Japanese Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7
Geometric Mean (Geometric Coefficient of Variation) [Milliliter]	135330.9 (5.5)

9. Secondary Outcome

Title	Cmax of Pyrimethamine in Healthy Caucasian Male Participants
Description	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	Healthy Caucasian Participants
Arm/Group Description	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7
Geometric Mean (Geometric Coefficient of Variation) [Nanogram per milliliter]	371.1 (10.0)

10. Secondary Outcome

Title	AUC (0-t) of Pyrimethamine in Healthy Caucasian Male Participants
Description	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	Healthy Caucasian Participants
Arm/Group Description	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7
Geometric Mean (Geometric Coefficient of Variation) [Hours* nanogram per milliliter]	41582.0 (26.9)

11. Secondary Outcome

Title	AUC (0-inf) of Pyrimethamine in Healthy Caucasian Male Participants
Description	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	Healthy Caucasian Participants
Arm/Group Description	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7
Geometric Mean (Geometric Coefficient of Variation) [Hours* nanogram per milliliter]	44869.1 (27.0)

12. Secondary Outcome

Title	AUC (0-24) of Pyrimethamine in Healthy Caucasian Male Participants
Description	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	Healthy Caucasian Participants
Arm/Group Description	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7
Geometric Mean (Geometric Coefficient of Variation) [Hours* nanogram per milliliter]	6930.8 (19.3)

13. Secondary Outcome

Title	Tmax of Pyrimethamine in Healthy Caucasian Male Participants
Description	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	Healthy Caucasian Participants
Arm/Group Description	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7
Median (Full Range) [Hours]	1.000

14. Secondary Outcome

Title	T1/2 of Pyrimethamine in Healthy Caucasian Male Participants
Description	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	Healthy Caucasian Participants
Arm/Group Description	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7
Mean (Standard Deviation) [Hours]	99.46 (20.745)

15. Secondary Outcome

Title	CL/F of Pyrimethamine in Healthy Caucasian Male Participants
Description	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	Healthy Caucasian Participants
Arm/Group Description	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7
Geometric Mean (Geometric Coefficient of Variation) [Milliliters per hour]	1114.4 (27.0)

16. Secondary Outcome

Title	Vd/F of Pyrimethamine in Healthy Caucasian Male Participants
Description	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population

Arm/Group Title	Healthy Caucasian Participants
Arm/Group Description	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7
Geometric Mean (Geometric Coefficient of Variation) [Milliliters]	157125.8 (16.8)

17. Secondary Outcome

Title	Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
Any AEs	2 28.6%	6 85.7%
Any SAEs	0 0%	0 0%

18. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
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 (0.395)	0.00 (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 (0.427)	0.00 (0.580)
Potassium, 96 hours, n=7, 7	0.00 (0.356)	-0.11 (0.515)
Potassium, 168 hours, n=7, 7	0.01 (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, 6	0.09 (0.402)	-0.22 (0.488)
Sodium, 24 hours, n=7, 7	-0.3 (3.55)	0.0 (2.83)
Sodium, 96 hours, n=7, 7	-0.6 (3.05)	1.0 (1.73)
Sodium, 168 hours, n=7, 7	-1.3 (2.63)	1.7 (1.25)
Sodium, 336 hours, n=7, 7	0.3 (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, 7	0.33 (0.772)	1.01 (1.110)
Urea, 96 hours, n=7, 7	0.26 (1.190)	-0.03 (0.660)
Urea, 168 hours, n=7, 7	0.41 (1.053)	-0.26 (0.885)
Urea, 336 hours, n=7, 7	-0.16 (0.896)	1.06 (1.726)
Urea, Follow up,(504 hours) n=7, 6	0.99 (1.995)	1.27 (1.317)

19. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
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, 7	0.7 (5.53)	-4.4 (8.16)
ALT, 336 hours, n=7, 7	0.9 (9.84)	-3.9 (2.79)
ALT, Follow up (504 hours), n=7, 6	0.4 (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, 7	0.3 (9.81)	-2.4 (5.86)
AST, Follow up (504 hours), n=7, 6	0.0 (4.16)	-1.5 (6.83)

20. Secondary Outcome

Title	Change From Baseline of Clinical Chemistry Parameters: Direct Bilirubin, Bilirubin, Creatinine.
Description	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)

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
Direct bilirubin, 24 hours, n=7, 7	0.7 (1.98)	0.6 (0.53)
Direct bilirubin, 96 hours, n=7, 7	0.4 (1.27)	0.7 (1.70)
Direct bilirubin, 168 hours, n=7, 7	0.6 (2.30)	0.9 (1.35)
Direct bilirubin, 336 hours, n=7, 7	-0.3 (1.60)	0.9 (1.95)
Direct bilirubin, Follow-up (504 hours), n=7, 6	-0.3 (1.50)	0.3 (1.97)
Bilirubin, 24 hours, n=7, 7	1.4 (5.16)	3.1 (4.56)
Bilirubin, 96 hours, n=7, 7	-0.6 (5.83)	2.4 (5.47)
Bilirubin, 168 hours, n=7, 7	0.7 (8.10)	1.0 (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, 7	21.7 (8.16)	26.6 (6.68)
Creatinine, 96 hours, n=7, 7	24.4 (5.06)	30.1 (7.84)
Creatinine, 168 hours, n=7, 7	20.9 (5.08)	24.6 (4.83)
Creatinine, 336 hours, n=7, 7	14.1 (6.18)	14.9 (4.71)
Creatinine, Follow up (504 hours), n=7, 6	5.6 (6.16)	9.5 (7.77)

21. Secondary Outcome

Title	Change From Baseline of Clinical Chemistry Parameters: Protein
Description	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)

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
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)

22. Secondary Outcome

Title	Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet and Leukocytes
Description	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)

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
Eosinophils, 24 hours, n=4, 3	-0.03 (0.096)	0.07 (0.058)
Eosinophils, 96 hours, n=4, 3	-0.03 (0.150)	0.00 (0.100)
Eosinophils, 168 hours, n=4, 3	0.00 (0.115)	0.00 (0.100)
Eosinophils, 336 hours, n=3, 3	0.00 (0.100)	0.00 (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 (0.528)	0.36 (0.251)
Lymphocytes, 96 hours, n=7, 7	-0.11 (0.508)	0.30 (0.277)
Lymphocytes, 168 hours, n=7, 7	-0.10 (0.574)	0.26 (0.276)
Lymphocytes, 336 hours, n=7, 7	-0.50 (0.616)	0.09 (0.363)
Lymphocytes, Follow up (504 hours), n=7, 6	-0.41 (0.441)	0.00 (0.514)
Monocytes, 24 hours, n=7, 7	-0.11 (0.107)	0.04 (0.113)
Monocytes, 96 hours, n=7, 7	-0.04 (0.190)	-0.01 (0.227)
Monocytes, 168 hours, n=7, 7	0.01 (0.186)	0.00 (0.153)
Monocytes, 336 hours, n=7, 7	-0.09 (0.177)	0.00 (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)

23. Secondary Outcome

Title	Change From Baseline in Hematology Parameter: Reticulocytes
Description	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)

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
24 hours, n= 7, 7	-0.0016 (0.00172)	0.0003 (0.00125)
96 hours, n=7, 7	0.0017 (0.00544)	-0.0006 (0.00162)
168 hours, n=7, 7	0.0013 (0.00577)	0.0009 (0.00212)
336 hours, n= 7, 7	-0.0011 (0.00430)	0.0003 (0.00335)
Follow up (504 hours), n=7, 6	-0.0013 (0.00368)	0.0017 (0.00308)

24. Secondary Outcome

Title	Change From Baseline in Hematology Parameter: Hematocrit
Description	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)

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
24 hours, n= 7, 7	0.001 (0.0135)	0.007 (0.0198)
96 hours, n=7, 7	0.009 (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)

25. Secondary Outcome

Title	Change From Baseline in Hematology Parameter: Hemoglobin
Description	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)

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
24 hours, n= 7, 7	2.0 (2.45)	3.0 (5.23)
96 hours, n=7, 7	2.6 (5.71)	0.0 (2.24)
168 hours, n=7, 7	0.0 (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)

26. Secondary Outcome

Title	Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin
Description	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)

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
24 hours, n= 7, 7	0.0 (0.00)	0.0 (0.00)
96 hours, n=7, 7	-0.4 (0.53)	0.0 (0.58)
168 hours, n=7, 7	0.0 (0.82)	-0.1 (0.69)
336 hours, n= 7, 7	0.1 (0.90)	-0.3 (0.76)
Follow up (504 hours), n=7, 6	0.0 (0.58)	-0.2 (0.41)

27. Secondary Outcome

Title	Change From Baseline in Hematology Parameter: Mean Corpuscular Volume
Description	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)

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
24 hours, n= 7, 7	-0.6 (0.98)	-0.7 (2.43)
96 hours, n=7, 7	0.1 (0.90)	-1.4 (1.40)
168 hours, n=7, 7	-0.3 (1.11)	-1.1 (1.35)
336 hours, n= 7, 7	0.4 (0.98)	-1.9 (1.68)
Follow up (504 hours), n=7, 6	0.4 (1.27)	-1.7 (1.21)

28. Secondary Outcome

Title	Change From Baseline in Hematology Parameter: Erythrocytes
Description	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)

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
24 hours, n= 7, 7	0.026 (0.0820)	0.100 (0.1943)
96 hours, n=7, 7	0.101 (0.1642)	0.006 (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)

29. Secondary Outcome

Title	Number of Participants With Abnormal Urinalysis Parameter
Description	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)

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
Ketones, 336 hours, ++	2 28.6%	0 0%
Ketones, 336 hours, trace	0 0%	1 14.3%
Ketones, follow up (504 hours), +	1 14.3%	0 0%
Occult blood, 336 hours, +	1 14.3%	0 0%
Occult blood, follow up, trace	0 0%	1 14.3%
Protein, Day -1, trace	0 0%	1 14.3%
Protein, 24 hours, trace	2 28.6%	3 42.9%
Protein, 96 hours, trace	2 28.6%	4 57.1%
Protein, 168 hours, trace	2 28.6%	1 14.3%
Protein, 336 hours, trace	3 42.9%	3 42.9%

30. Secondary Outcome

Title	Specific Gravity at Indicated Time Points
Description	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)

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
Day -1, n=7, 7	1.0127 (0.00856)	1.0177 (0.00720)
24 hours, n=7, 7	1.0214 (0.00621)	1.0256 (0.00665)
96 hours, n=7, 7	1.0211 (0.00832)	1.0236 (0.00550)
168 hours, n=7, 7	1.0211 (0.00821)	1.0207 (0.00562)
336 hours, n=7, 7	1.0193 (0.00871)	1.0246 (0.00945)
Follow up (504 hours), n=7, 6	1.0183 (0.00720)	1.0222 (0.00728)

31. Secondary Outcome

Title	Urine Potential of Hydrogen (pH) at Indicated Time Points
Description	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)

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
Day -1, n=7, 7	6.21 (0.699)	6.86 (1.144)
24 hours, n=7, 7	5.86 (0.244)	5.79 (0.567)
96 hours, n=7, 7	5.79 (0.393)	6.07 (0.345)
168 hours, n=7, 7	5.93 (0.535)	6.07 (0.450)
336 hours, n=7, 7	6.00 (0.577)	6.00 (0.408)
Follow up (504 hours), n=7, 6	6.43 (0.673)	6.08 (0.492)

32. Secondary Outcome

Title	Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
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 (6.50)	2.0 (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 (5.93)	1.3 (7.04)
SBP, 12 hours, n=7, 7	1.4 (3.41)	1.0 (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 (9.96)	2.6 (8.48)
SBP, 120 hours, n=7, 7	-6.3 (5.53)	0.9 (7.88)
SBP,144 hours, n=7, 7	-6.6 (7.30)	-3.3 (6.52)
SBP, 168 hours, n=7, 7	0.4 (8.18)	0.9 (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)

33. Secondary Outcome

Title	Change From Baseline in Pulse Rate
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
4 hours, n=7, 7	3.6 (5.19)	4.7 (6.95)
12 hours, n=7, 7	5.0 (11.45)	10.1 (6.74)
24 hours, n=7, 7	3.4 (8.38)	-5.0 (4.36)
48 hours, n=7, 7	3.4 (18.12)	-0.3 (4.39)
72 hours, n=7, 7	4.9 (11.26)	-0.3 (4.15)
96 hours, n=7, 7	1.4 (13.44)	0.6 (3.21)
120 hours, n=7, 7	1.1 (9.58)	2.0 (6.11)
144 hours, n=7, 7	0.1 (16.74)	-0.1 (3.24)
168 hours, n=7, 7	4.4 (17.62)	7.1 (7.20)
336 hours, n=7, 7	1.0 (17.61)	1.6 (7.50)
504 hours, n=7, 6	-2.1 (18.52)	2.2 (6.79)

34. Secondary Outcome

Title	Change From Baseline in Temperature
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
4 hours, n=7, 7	-0.01 (0.195)	0.27 (0.095)
12 hours, n=7, 7	0.04 (0.172)	0.26 (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 (0.186)	0.01 (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)

35. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
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 (33.80)	0.3 (5.41)
PR Interval, 504 hours, n=7, 6	-7.3 (10.05)	2.2 (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, 7	0.3 (2.50)	-2.0 (3.96)
QRS duration, 48 hours, n=7, 7	3.1 (11.16)	0.4 (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, 7	4.3 (25.79)	-7.3 (7.48)
QT interval, 48 hours, n=7, 7	2.3 (21.55)	-14.7 (13.50)
QT interval, 504 hours, n=7, 6	14.7 (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, 7	11.6 (40.64)	-2.9 (12.88)
QTcF interval, 504 hours, n=7, 6	6.7 (12.84)	-2.2 (9.64)

36. Secondary Outcome

Title	Change From Baseline of ECG Parameter: ECG Mean Heart Rate
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles).

Arm/Group Title	Healthy Japanese Participants	Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.	Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
Measure Participants	7	7
4 hours, n=7, 7	-2.3 (11.37)	6.0 (6.32)
12 hours, n=7, 7	2.3 (19.91)	7.1 (5.37)
24 hours, n=7, 7	-5.3 (19.67)	3.1 (6.72)
48 hours, n=7, 7	6.7 (15.64)	5.0 (5.32)
504 hours, n=7, 6	-7.1 (25.71)	3.2 (7.65)

Adverse Events

Time Frame	Serious adverse events (SAEs) and non-serious AEs were collected up to Day 23
Adverse Event Reporting Description	Non-serious AEs and SAEs for Safety Population was reported
Arm/Group Title	Healthy Japanese Participants		Healthy Caucasian Participants
Arm/Group Description	Healthy Japanese male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.		Healthy Caucasian male participants received a single oral dose of Pyrimethamine 50 mg tablet in the fasted state co-administered with calcium folinate 15 mg tablet on Day 1. Oral calcium folinate was administered once daily until Day 8 along with 240 mL of water.
All Cause Mortality
	Healthy Japanese Participants		Healthy Caucasian Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)
Serious Adverse Events
	Healthy Japanese Participants		Healthy Caucasian Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Healthy Japanese Participants		Healthy Caucasian Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/7 (28.6%)		6/7 (85.7%)
Gastrointestinal disorders
Abdominal discomfort	0/7 (0%)	0	1/7 (14.3%)	1
Nausea	0/7 (0%)	0	1/7 (14.3%)	1
General disorders
Catheter site pain	0/7 (0%)	0	1/7 (14.3%)	1
Infections and infestations
Folliculitis	0/7 (0%)	0	1/7 (14.3%)	1
Upper respiratory tract infection	0/7 (0%)	0	1/7 (14.3%)	1
Viral infection	1/7 (14.3%)	1	0/7 (0%)	0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	0/7 (0%)	0	1/7 (14.3%)	1
Nervous system disorders
Headache	0/7 (0%)	0	1/7 (14.3%)	1
Tension headache	1/7 (14.3%)	1	0/7 (0%)	0
Skin and subcutaneous tissue disorders
Dry skin	1/7 (14.3%)	1	0/7 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.