OPEN-LABEL, CROSSOVER EXPLORATORY STUDY TO ASSESS THE DOSE DEPENDENT EFFECT OF PYRIMETHAMINE ON EXOGENOUS AND ENDOGENOUS MATE1/2K SUBSTRATES

JRCT ID: jRCTs031180125

Registered date:18/02/2019

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: None
• Date of first enrollment: 08/04/2019
• Target sample size: 12
• Study type: Interventional

Intervention(s)

Period I: On the day before administration of study drugs, the baseline data of endogenous substrates will be obtained by administrating placebo (excipient: lactose). A single dose of the probe drug cocktail (metformin) will be orally administered to subjects on the day of dosing.
Periods II, III and IV: Pyrimethamine will be given 1 hour prior to administration of probe drug orally. Subjects will be randomized to one of two of the following pyrimethamine (PYR) treatment sequences:
Sequence 1: Period II PYR 10 mg -> Period III PYR 25 mg -> Period IV PYR 75 mg
Sequence 2: Period II PYR 25 mg -> Period III PYR 10 mg -> Period IV PYR 75 mg

<Drug Dose>
Metformin: 500 mg
Pyrimethamine: 10, 25, or 75 mg

Outcome(s)

Primary Outcome

- Kinetic parameters of endogenous substrates during administration / non-administration of metformin (OCT 2 and MATE probe), pyrimethamine (MATE inhibitor)
- Measurement subjects: Pharmacokinetics (PK) of endogenous substrates metformin, pyrimethamine of other drug transporters and drug metabolizing enzymes including creatinine, N1-methyl nicotinamide, thiamine, other OCT2 and MATE 1 / 2K in plasma and urine, Evaluation of
- Evaluation of pharmacokinetics (PK) of metformin, pyrimethamine
- Measurement target: metformin in plasma and urine, pyrimethamine in plasma

Secondary Outcome

- Genotyping (e.g., MATE1, MATE2-K, and OCT2) for PK of metformin, and endogenous substrates
- Concentrations of proteins in the plasma and urine specimens that could regulate the activities of drug transporters, and PK of metformin, and endogenous substrates

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: < 40age old
• Gender: Male

Include criteria

a)Healthy Japanese men at >=20 but <40 years of age when the consent was obtained.
b)Persons whose body mass index (BMI) is >=18.5 but <25.0 at screening.
c)Persons who were judged appropriate as subjects by the investigator (sub-investigator) based on medical history and physical exam and laboratory tests at screening.
d)Subjects who can understand and comply with the protocol and from whom the written consent based on his or her own free will can be obtained.

Exclude criteria

a) Persons with a history of hypersensitivity to metformin or biguanide drug, pyrimethamine
b) Persons who are contraindicated for administration of metformin
c) Persons who are in the following state [Persons who are liable to cause lactic acidosis.]
(1) history of lactic acidosis
(2) renal dysfunction of moderate or higher
(3) dialysis patients (including peritoneal dialysis)
(4) severe liver dysfunction,
(5) shock, heart failure, myocardial infarction
(6) excessive alcohol intake
(7) Patients with gastrointestinal disorders such as vomiting, dehydration or diarrhea in which dehydration are a concern.
-Patients with severe ketosis, diabetic coma or precoma, type 1 diabetes [infusion, correction of rapid hyperglycemia by insulin is essential.]
-Severe infection, patients before and after surgery, patients with severe trauma [Administration of this drug is not suitable because it is desired to control blood glucose by insulin injection. Also, it is liable to cause lactic acidosis.]
-Patients with malnutrition, starvation, weakness, pituitary dysfunction or adrenal insufficiency
[May cause hypoglycemia. ]
-Persons who are contraindication of pyrimethamine administration or need careful administration
-Patients with megaloblastic anemia based on folate deficiency, patients with blood disorders or previous medical history, people with deficiency of folic acid or abnormal metabolism
-Person or parents, brothers who have a constitution prone to allergic symptoms such as bronchial asthma, rash, urticaria, or who have a history of hypersensitivity to other drugs.[Because there is description in interview form of fansidar (a combination agent containing sulphadoxin 500 mg and pyrimethamine 25 mg in 1 tablet, not single agent of pyrimethamine)]
d) Persons with lactose intolerance
e) Persons with hypotension (systolic blood pressure: <90 mmHg) or hypertension (systolic blood pressure: >=160 mmHg)
f) Persons who donated or lost 200 mL (1 unit) of blood within 4 weeks before administration of study drugs or 400 mL (2 units) of blood within 3 months before administration of study drugs.
g) Persons with a medical history/complication of severe nerve disease, cerebrovascular disease, liver disease, kidney disease, endocrine disease, cardiovascular disease, gastrointestinal disease (including digestive system disease which is considered to affect the absorption of study drugs), respiratory disease, metabolic disease, and anemia.
h) Persons with estimated creatinine clearance (eClcr, Cockcroft-Gault Equation) < 90 mL/min.
The person with low renal excretion ability of medicines
i) Persons who have been confirmed of a clinically severe abnormality based on medical examination or physical examination by the investigator or subinvestigator.
j) Persons with a clinically severe disease within 30 days before administration of study drugs.
k) Persons who took drugs, health food including St.John's wort, food 14 days prior to dosing and beverages including grapefruit, orange and apple (including food containing them), and nutritional supplements 7 days prior to dosing and cannot comply with prohibition of taking them during the study.
l) Persons who are smoking or taking nicotine within 30 days before administration of study drugs and who cannot comply with smoking cessation during the study period.
m) Persons who took alcohol/caffeine-containing food on the day before hospitalization in each study period and cannot comply with prohibition of taking them until the day of discharge in each study period.
n) Persons who tested positive in an alcohol breathe test/urine drug test at screening.
o) Persons who cannot discontinue the use of drugs other than study drugs from 2 weeks before administration of study drugs until the study completion.
p) Persons who are positive to hepatitis B surface (HBs) antigens, hepatitis C (HCV) antibodies, or human immunodeficiency virus (HIV) antigens/antibodies.
q) Other persons who were judged inappropriate by the investigator or subinvestigator.

Related Information

• Primary Sponsor: Furihata Kenichi
• Source(s) of Monetary Support: Pfizer Inc.