Absolute BA and OZ439 PK Effect of Different OZ439 Dose Volumes and Cobicistat Co-administration Study
Condition: Malaria
MeSH terms: Malaria
Intervention: Single oral dose of 800 mg OZ439; Single oral dose of 400 mg OZ439; Single oral dose of cobicistat; iv infusion of [14C]-OZ439
Intervention description: Single oral dose of 800 mg OZ439; Single oral dose of 400 mg OZ439; Single oral dose of 150 mg cobicistat; 15-minute 10-mL iv infusion of 100 μg [14C]-OZ439
Intervention MeSH terms: Cobicistat; Artefenomel
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Part1: Open label, one treatment Part 2: Open-label, randomized, single-dose, 3-way cross-over study
Masking: None (Open Label)
Enrollment: 26.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      This study is an open-label, two-part study to determine the absolute bioavailability (BA) of
      OZ439 using simultaneous intravenous [14C]-OZ439 microdose/800mg oral dosing and to
      investigate the pharmacokinetics (PK) of OZ439 granules administered as single doses
      suspended in different volumes and when co-administered with a single dose of Cobicistat, a
      strong CYP3A4 inhibitor, to healthy subjects in fasted state.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Body mass index (BMI) : 18.0-30.0 kg/m2, inclusive, at screening

          -  Weight : >50 kg, at screening

          -  Status : healthy subjects

          -  Female subjects must be of non-childbearing potential (either surgically sterilized or
             physiologically incapable of becoming pregnant, or post-menopausal [defined as
             spontaneous amenorrhoea for at least 1 year or spontaneous amenorrhoea for at least 6
             months confirmed by a follicle stimulating hormone (FSH) result indicating a
             post-menopausal status]) and have a negative pregnancy test at screening and at (each)
             admission to the clinical research center. As all female subjects must be of
             non-childbearing potential, they are not required to use any contraception during this
             study.

          -  Male subjects must use adequate contraception and not donate sperm from (first)
             admission to the clinical research center until 90 days after the follow-up visit.
             Adequate contraception for the male subject (and his female partner) is defined as
             surgical sterilization (vasectomy), using hormonal contraceptives (implantable, patch,
             oral, injectable) or an intrauterine device or system combined with at least 1 of the
             following forms of contraception (barrier method): a diaphragm or cervical cap, or a
             condom. Also, total abstinence, in accordance with the lifestyle of the subject is
             acceptable.

          -  Must have QTcF ≤450 ms and QTcB ≤450 ms (male subjects); QTcF ≤470 ms and QTcB ≤470 ms
             (female subjects), and PR-interval ≤200 ms for screening, and Day -1 and pre-dose ECG
             measurements of the (first) treatment period

          -  Ability and willingness to abstain from alcohol and methylxanthine-containing
             beverages or food (coffee, tea, cola, chocolate, energy drinks) from 48 hours prior to
             (each) admission to the clinical research center

          -  Willing and able to communicate and participate in the whole study

          -  Willing and able to sign the ICF

        Exclusion Criteria:

          -  A subject who meets any of the following exclusion criteria will not be eligible for
             inclusion in the study:

          -  Male subjects who have currently pregnant partners or who have partners planning to be
             pregnant in the 90 days after discharge

          -  Evidence or history of clinically significant oncological, pulmonary, chronic
             respiratory, hepatic, cardiovascular, hematological, metabolic, neurological,
             immunological, nephrological, endocrine or psychiatric disease, or current infection

          -  Clinically relevant (as decided by the Principal Investigator [PI]) abnormalities in
             the 12-lead ECG, including asymptomatic bundle branch block

          -  Family history of sudden death or of congenital prolongation of the QTc-interval or
             known congenital prolongation of the QTc-interval or any clinical condition known to
             prolong the QTc-interval

          -  History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia,
             heart rate ≤39 beats per minute (bpm)

          -  Electrolyte disturbances, particularly hypokalemia, hypocalcemia or hypomagnesemia

          -  Any condition that could possibly affect drug absorption, e.g. gastrectomy or diarrhea

          -  History of post-antibiotic colitis

          -  History of any drug or alcohol abuse in the past 2 years prior to screening

          -  Subjects who regularly smoke more than 5 cigarettes a day

          -  Receipt of an investigational drug or participation in another clinical research study
             within 90 days prior to the first dose of study drug

          -  Subjects who are PRA employees, or immediate family members of PRA or Sponsor
             employees

          -  Subjects who have previously been enrolled in this study

          -  Use of moderate/strong inhibitors or inducers of CYP cytochromes or transporters
             within 30 days or 5 half-lives (whichever is longer) prior to the first dose of study
             drug

          -  Consumption of grapefruit, grapefruit juice or grapefruit-related citrus fruits (e.g.
             Seville oranges, pomelos) within 14 days prior to the first dose of study drug

          -  Use of prescription or non-prescription drugs and dietary supplements within 7 days or
             5 half-lives (whichever is longer) prior to the first dose of study drug. With the
             exception of paracetamol (which may be used incidentally or for a short-term treatment
             at a maximum dose of 2 g per day) and hormone replacement therapy

          -  Use of herbal supplements within 30 days prior to the first dose of study drug

          -  Positive hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody or
             HIV-1 or HIV-2 antibody results

          -  Clinically significant abnormal biochemistry, hematology or urinalysis as judged by
             the PI. In case of doubt the PI will discuss this with the medical monitor

          -  Positive urine drug screen result at screening or admission to the clinical research
             center

          -  Serious adverse reaction or serious hypersensitivity to any drug or the formulation
             excipients

          -  Presence or history of allergy requiring treatment. Hayfever is allowed unless it is
             active

          -  Donation or loss of >100 mL of blood within 90 days prior to drug administration

          -  Regular alcohol consumption in males >21 units per week and females >14 units per week
             (1 unit = 250 mL beer, 25 mL of 40% spirit or 125 mL of wine)

          -  Subjects who do not have suitable veins for multiple venepunctures/cannulation as
             assessed by the PI or delegate at screening

          -  Failure to satisfy the PI of fitness to participate for any other reason