Phase I Study of Pyrimethamine in Healthy Japanese and Caucasian Subjects

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Toxoplasmosis

Intervention / Treatment
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* Drug: Pyrimethamine
* Drug: Calcium folinate


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy Japanese male subjects<br>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<br>* 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.<br>Drug: Calcium folinate<br>* 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.<br>|
| Experimental: Healthy Caucasian male subjects<br>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<br>* 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.<br>Drug: Calcium folinate<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | Up to Day 23 | 
| 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. | Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours) | 
| 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. | Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours) | 
| 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. | Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours) | 
| 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. | Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours) | 
| 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. | Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours) | 
| 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. | Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours) | 
| 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. | Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours) | 
| 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. | Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours) | 
| 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. | Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours) | 
| 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. | Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours) | 
| 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. | Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours) | 
| 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. | Day -1, 24, 96, 168, 336 and follow up (504 hours) | 
| 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. | Day -1, 24, 96, 168, 336 hours and follow up (504 hours) | 
| 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). | Day -1, 24, 96, 168, 336 hours and follow up (504 hours) | 
| 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. | Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours | 
| 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. | Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours | 
| 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. | Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours | 
| 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. | Baseline (Pre-dose on Day 1), 4, 12, 24, 48, and 504 hours | 
| 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. | Baseline (Pre-dose on Day 1), 4, 12, 24, 48, and 504 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Japanese, Caucasian, pharmacokinetics, pyrimethamine, toxoplasmosis