Phase I Study of Pyrimethamine in Healthy Japanese and Caucasian Subjects
Condition: Toxoplasmosis
MeSH terms: Toxoplasmosis
Intervention: Pyrimethamine; Calcium folinate
Intervention description: 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.; 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.
Intervention MeSH terms: Leucovorin; Pyrimethamine; Calcium; Levoleucovorin
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: Male
Minimum age: 20 Years
Maximum age: 64 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Japanese; Caucasian; pharmacokinetics; pyrimethamine; toxoplasmosis

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.