Clinical trial NCT03258762: Phase I Study of Pyrimethamine in Healthy Japanese and Caucasian Subjects
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Toxoplasmosis
Keywords: Japanese
Caucasian
pharmacokinetics
pyrimethamine
toxoplasmosis
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-08-23
Enrollment: 14
Sex: MALE
Minimum age (years): 20
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Maximum Observed Concentration (Cmax) of Pyrimethamine in Healthy Japanese Male Participants
timeFrame: 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
measure: Area Under the Concentration-time Curve From Time 0 to t (AUC[0-t]) of Pyrimethamine in Healthy Japanese Male Participants
timeFrame: 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
measure: Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) of Pyrimethamine in Healthy Japanese Male Participants
timeFrame: 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
measure: Area Under the Concentration-time Curve From Time 0 to 24 (AUC[0-24]) of Pyrimethamine in Healthy Japanese Male Participants
timeFrame: 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
measure: Terminal Half-life (t1/2) of Pyrimethamine in Healthy Japanese Male Participants
timeFrame: 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
measure: Time to Maximum Observed Concentration (Tmax) of Pyrimethamine in Healthy Japanese Male Participants
timeFrame: 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
measure: Apparent Clearance Following Oral Dosing (CL/F) of Pyrimethamine in Healthy Japanese Male Participants
timeFrame: 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
measure: Apparent Volume of Distribution Following Oral Dosing (Vd/F) of Pyrimethamine in Healthy Japanese Male Participants
timeFrame: Pre-dose, 1, 2, 4, 6, 12 hours post-dose on Day 1, Day 2, Day 3, Day 4, Day 6, Day 8, Day 15 and Day 22
Secondary outcomes:
measure: Cmax of Pyrimethamine in Healthy Caucasian Male Participants
timeFrame: 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
measure: AUC (0-t) of Pyrimethamine in Healthy Caucasian Male Participants
timeFrame: 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
measure: AUC (0-inf) of Pyrimethamine in Healthy Caucasian Male Participants
timeFrame: 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
measure: AUC (0-24) of Pyrimethamine in Healthy Caucasian Male Participants
timeFrame: 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
measure: Tmax of Pyrimethamine in Healthy Caucasian Male Participants
timeFrame: 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
measure: T1/2 of Pyrimethamine in Healthy Caucasian Male Participants
timeFrame: 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
measure: CL/F of Pyrimethamine in Healthy Caucasian Male Participants
timeFrame: 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
measure: Vd/F of Pyrimethamine in Healthy Caucasian Male Participants
timeFrame: 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
measure: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: Up to Day 23
measure: Change From Baseline of Clinical Chemistry Parameters: Glucose, Sodium, Calcium, Potassium, and Urea.
timeFrame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
measure: Change From Baseline of Clinical Chemistry Parameters: Alkaline Phosphatase, Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST)
timeFrame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
measure: Change From Baseline of Clinical Chemistry Parameters: Direct Bilirubin, Bilirubin, Creatinine.
timeFrame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
measure: Change From Baseline of Clinical Chemistry Parameters: Protein
timeFrame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
measure: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet and Leukocytes
timeFrame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
measure: Change From Baseline in Hematology Parameter: Reticulocytes
timeFrame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
measure: Change From Baseline in Hematology Parameter: Hematocrit
timeFrame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
measure: Change From Baseline in Hematology Parameter: Hemoglobin
timeFrame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
measure: Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin
timeFrame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
measure: Change From Baseline in Hematology Parameter: Mean Corpuscular Volume
timeFrame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
measure: Change From Baseline in Hematology Parameter: Erythrocytes
timeFrame: Baseline (Day -1), 24, 96, 168, 336 hours and follow up (504 hours)
measure: Number of Participants With Abnormal Urinalysis Parameter
timeFrame: Day -1, 24, 96, 168, 336 and follow up (504 hours)
measure: Specific Gravity at Indicated Time Points
timeFrame: Day -1, 24, 96, 168, 336 hours and follow up (504 hours)
measure: Urine Potential of Hydrogen (pH) at Indicated Time Points
timeFrame: Day -1, 24, 96, 168, 336 hours and follow up (504 hours)
measure: Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
timeFrame: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours
measure: Change From Baseline in Pulse Rate
timeFrame: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours
measure: Change From Baseline in Temperature
timeFrame: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, 72, 96, 120, 144, 168, 336 and 504 hours
measure: 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
timeFrame: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, and 504 hours
measure: Change From Baseline of ECG Parameter: ECG Mean Heart Rate
timeFrame: Baseline (Pre-dose on Day 1), 4, 12, 24, 48, and 504 hours
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: GSK Investigational Site
state: Victoria
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.