This study will be a single-center, phase I, randomized, open, in fed condition, parallel,
single dose study to evaluate the pharmacokinetics and the safety, tolerability of
Atovaquone/proguanil combination tablets and atovaquone suspension in Japanese healthy male
subjects.
Serial blood samples will be collected for the determination of the plasma concentration of
atovaquone, proguanil and cycloguanil after dosing of atovaquone 1000mg/proguanil 400 mg and
the plasma atovaquone concentration of atovaquone 750 and 1500 mg. Safety assessments will
be performed for each treatment group.
CYP2C19 contribute to proguanil metabolism. CYP2C19 genotype will be determined in
atovaquone/proguanil dosing group.
Inclusion Criteria:
- Healthy as defined as being free from clinically significant illness or disease as
determined by a responsible and experienced physician, based on a medical evaluation
including medical history, physical examination, vital sign, laboratory tests and
ECG.
- Japanese healthy male between 20 and 55 years of age inclusive, at the time of
signing the informed consent.
- Body weight => 50 kg and BMI within the range 18. 5- 25 kg/m2
- Non-smoker or ex-smoker having ceased smoking for at least 6 months. (inclusive).
- ALT, alkaline phosphatase and bilirubin below the upper limit of normal (ULN)
- Single QTcB< 450 msec.
- Vital sign within the following ranges; Systolic blood pressure: < 90 mmHg or > 140
mmHg, Diastolic blood pressure: < 45 mmHg or > 90 mmHg, Plus rate: < 45 bpm or > 100
bpm, Body temperature: 37. 5 C
- Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form.
Exclusion Criteria:
- A positive results of syphilis, HBs antigen, HCV antibody, HIV antibody and HTLV-1
antibody at the time of screening.
- History of any cardiac diseases irrespective of with or without symptom.
- An episode of cardiac syncope within one year before screening period.
- History/evidence of clinically significant pulmonary diseases and
hyper/hypo-thyroidism.
- Current or chronic history of liver disease, or known hepatic or biliary
abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- A positive pre-study drug screen.
- History of regular alcohol consumption exceeding, on average, 14 drinks/week for men
(1 drink = 5 ounces (150 mL) of wine or 350 mL of beer or 1. 5 ounces (45 mL) of 80
proof distilled spirits) within 6 months of screening.
- The subject had participated in a clinical study or post-marketing study with an
investigational or a non-investigational product during the previous 4 months
preceding the administration of study medication of this study.
- The subject had participated in a clinical study or post-marketing study with an
investigational or a non-investigational product during the previous 4 months
preceding the administration of study medication of this study.
- Exposure to more than four new chemical entities within 12 months prior to the first
dosing day.
- Unable to refrain from the use of alcohol, prescription or non-prescription drugs,
including vitamins, herbal and dietary supplements within 14 days or 5 half-lives
(whichever is longer) prior to the first dose of study medication.
- History of sensitivity to any of the study medications, or components thereof or a
history of drug or other allergy excluding pollen allergy without current symptoms.
- Where participation in the study would result in donation of blood or blood products
in excess of 400 mL within a 4 month or 200 mL within 2 month.
- Unwillingness or inability to follow the procedures outlined in the protocol.
- Subject is mentally or legally incapacitated.
