Last updated: 07/17/2024 17:18:14
Phase I study of Pyrimethamine in healthy Japanese and Caucasian Subjects
EudraCT ID
Not applicable
EU CT Number
Not applicable
Trial status
Completed
Completed
Trial overview
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
Trial description: 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.
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
None (Open Label)
Allocation:
Non-randomized
Primary outcomes:
Maximum observed concentration (Cmax) of Pyrimethamine in healthy Japanese male subjects
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
Area under the concentration-time curve from time 0 to t [AUC(0-t)] of Pyrimethamine in healthy Japanese male subjects
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
Area under the concentration-time curve from time 0 to infinity [AUC(0-inf)] of Pyrimethamine in healthy Japanese male subjects
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
Area under the concentration-time curve from time 0 to 24 [AUC(0-24)] of Pyrimethamine in healthy Japanese male subjects
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
Time to maximum observed concentration (tmax) of Pyrimethamine in healthy Japanese male subjects
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
Terminal half-life (t1/2) of Pyrimethamine in healthy Japanese male subjects
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
Apparent clearance following oral dosing (CL/F) of Pyrimethamine in healthy Japanese male subjects
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
Apparent volume of distribution following oral dosing (Vd/F) of Pyrimethamine in healthy Japanese male subjects
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:
Cmax of Pyrimethamine in healthy Caucasian male subjects
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
AUC(0-t) of Pyrimethamine in healthy Caucasian male subjects
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
AUC(0-inf) of Pyrimethamine in healthy Caucasian male subjects
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
AUC(0-24) of Pyrimethamine in healthy Caucasian male subjects
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
tmax of Pyrimethamine in healthy Caucasian male subjects
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
t1/2 of Pyrimethamine in healthy Caucasian male subjects
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
CL/F of Pyrimethamine in healthy Caucasian male subjects
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
Vd/F of Pyrimethamine in healthy Caucasian male subjects
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
Number of subjects with adverse events (AEs) and serious adverse events (SAEs)
Timeframe: Up to Day 22
Change from Baseline in oral temperature
Timeframe: Baseline and up to Day 22
Change from Baseline in pulse rate
Timeframe: Baseline and up to Day 22
Change from Baseline in blood pressure
Timeframe: Baseline and up to Day 22
Change from Baseline in electrocardiogram (ECG) values
Timeframe: Baseline and up to Day 22
Number of subjects with abnormal hematology parameters
Timeframe: Up to Day 22
Number of subjects with abnormal Clinical chemistry parameters
Timeframe: Up to Day 22
Number of subjects with abnormal urine parameters
Timeframe: Up to Day 22
Interventions:
Drug: Pyrimethamine
Drug: Calcium folinate
Enrollment:
14
Observational study model:
Not applicable
Primary completion date:
2017-19-11
Time perspective:
Not applicable
Clinical publications:
Takayuki Iida , Romina Nand , Hiroko Ino , Hirofumi Ogura , Hiroshi Itoh , Harue Igarashi , Yotaro Numachi , Annette Gross. Evaluation of the pharmacokinetics, safety, and tolerability of single oral dose pyrimethamine (DARAPRIM®) in healthy male subjects of Japanese and European ancestry. Clin Pharmacol Drug Devel. 2020
DOI: 10.1002/cpdd.771
PMID: 31950646
Medical condition
Toxoplasmosis
Product
pyrimethamine
Collaborators
Not applicable
Study date(s)
September 2017 to November 2017
Type
Interventional
Phase
1
Participation criteria
Sex
Male
Age
20 - 64 years
Accepts healthy volunteers
Yes
- 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.
- 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).
Inclusion and exclusion 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.
Trial location(s)
Study documents
Protocol
Available language(s): English
Statistical analysis plan
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Completed
Actual primary completion date
2017-19-11
Actual study completion date
2017-19-11
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
Additional information
Not applicable
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