Phase I Study of Pyrimethamine in Healthy Japanese and Caucasian Subjects

NCT03258762 | Completed Phase 1 Results

• 1 other identifier: 204678
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

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.

Conditions

Toxoplasmosis

Keywords

Japanese; Caucasian; pharmacokinetics; pyrimethamine; toxoplasmosis

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (28)

• 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

• 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

• 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

• 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

• 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

Study Arms (2)

Healthy Japanese male subjects

EXPERIMENTAL

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

Drug: Pyrimethamine; Drug: Calcium folinate

Healthy Caucasian male subjects

EXPERIMENTAL

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

Drug: Pyrimethamine; Drug: Calcium folinate

Interventions

Pyrimethamine DRUG

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.

Healthy Caucasian male subjects; Healthy Japanese male subjects

Calcium folinate DRUG

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.

Healthy Caucasian male subjects; Healthy Japanese male subjects

Eligibility Criteria

• Age: 20 Years - 64 Years
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Melbourne, Victoria, 3004, Australia

Location

Related Publications (1)

• 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.

  PMID: 31950646 BACKGROUND

MeSH Terms

Conditions

Toxoplasmosis

Interventions

Pyrimethamine; Leucovorin

Condition Hierarchy (Ancestors)

Coccidiosis; Protozoan Infections; Parasitic Diseases; Infections

Intervention Hierarchy (Ancestors)

Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 21, 2017
• First Posted: August 23, 2017
• Study Start: September 25, 2017
• Primary Completion: November 19, 2017
• Study Completion: November 19, 2017
• Last Updated: March 27, 2020
• Results First Posted: March 27, 2019

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

AU (1)