Healthy Volunteer Study of the Pharmacokinetics of Oral Piperaquine With OZ439 + TPGS Formulation in the Fasted State
Condition: Malaria
MeSH terms: Malaria
Intervention: PQP tablets 960mg; PQP tablets 1440mg; OZ439+TPGS 800mg; OZ439 PIB 800mg
Intervention description: Piperaquine phosphate tablets 960mg; Piperaquine phosphate tablets 1440mg; OZ439+TPGS prototype formulation 800mg; OZ439 Powder in Bottle Aqueous Solution 800mg
Intervention MeSH terms: Artefenomel
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 24.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: pharmacokinetics; safety; tolerability; bioavailability

Summary:

      Piperaquine tablets (coated) + OZ439 granules + TPGS granules will be co-administered in
      Phase IIb (adults). However, safety and PK data (for OZ439 plus piperaquine) were obtained
      using piperaquine tablets plus OZ439 as Powder in Bottle with milk. Piperaquine has not yet
      been administered together with TPGS. Co-administration of piperaquine plus OZ439 as Powder
      in Bottle (PIB) with milk results in an increase in OZ439 exposure (current estimate ~ 70%
      due to a small drug drug interaction).

      This study investigates the exposure of piperaquine and OZ439 when co-administered as
      piperaquine phosphate tablets and OZ439 + TPGS prototype (a formulation close to that of
      Phase IIb, but not identical), in order to select the appropriate doses for Phase IIb. The
      reference treatment is piperaquine phosphate tablets + OZ439 Powder in Bottle + full fat milk
    

Eligibility criteria:

        Inclusion Criteria:

          1. Healthy male/female of any race aged 18-55 years at screening

          2. Body Mass Index 18-30kg/m2; body weight >50kg but no more than 100kg at screening

          3. Females with negative pregnancy test at screening and admission, non-lactating and of
             non-child bearing potential confirmed

          4. Agree to use acceptable methods of contraception

          5. Should not donate egg and sperm from the time of administration of treatment or study
             medication until 3 months following dose of study medication

          6. Must be capable of understanding and complying with the requirements of the protocol
             and must have signed the informed consent form prior to undergoing any study-related
             procedures

        Exclusion Criteria:

          1. Male subjects with a female partner(s) who is (are) pregnant or lactating from the
             time of the administration of study medication

          2. Has a clinically significant disease or any condition or disease that might affect
             drug absorption, distribution or excretion, e.g. gastrectomy, diarrhoea.

          3. History of allergic reactions to artemisinin-based compounds, 4-aminoquinolines such
             as piperaquine or any other clinically relevant allergy to drugs or food.

          4. Any clinically relevant history of cow's milk intolerance/allergy.

          5. Any clinically significant abnormal laboratory, vital signs or other safety findings
             as determined by medical history, physical examination or other evaluations conducted
             at screening or on admission. Exception is PR, QTcB, QTcF, cardiac rhythm, liver
             function tests and haemoglobin that must be within the normal reference range at
             screening and on admission.

          6. History or current evidence of any clinically relevant cardiovascular, pulmonary,
             hepatic, renal, gastrointestinal (excluding appendectomy and cholecystectomy),
             haematological, endocrinological, immunological, metabolic, neurological, oncological,
             psychiatric, urological or other disease, or current infection

          7. History of post-antibiotic colitis

          8. Electrocardiogram abnormalities in the standard 12-lead (at screening) and/or 24-hour
             5 lead Holter (at screening) which in the opinion of the Investigator is clinically
             relevant or will interfere with the analysis

          9. A history of clinically significant electrocardiogram abnormalities, or any of the
             following abnormalities at screening or admission:

               -  PR >200 msec

               -  QRS complex >120 msec

               -  QTcB or QTcF >450 msec or shortened QTcB or QTcF less than 340 msec for males and
                  females or family history of long QT syndrome or sudden death

               -  Any degree of heart block (such as first, second or third degree atrioventricular
                  block, incomplete, full or intermittent bundle branch block)

               -  Abnormal T wave morphology / prominent U waves

               -  Potassium levels out of the normal range at screening and prior to dosing

         10. Positive results in any of the serology tests for Hepatitis B Surface Antigen, anti
             Hepatitis core antibody, Hepatitis C antibodies, and Human Immunodeficiency Virus 1
             and 2 antibodies

         11. Confirmed positive results from urine drug screen (amphetamines, benzodiazepines,
             cocaine, cannabinoids, opiates, barbiturates, and methadone) or from the alcohol
             breath test at screening and admission

         12. History or clinical evidence of alcohol abuse, or any recreational drug abuse within
             the 2 years prior to screening

         13. Mentally handicapped

         14. Participation in a drug trial within 90 days prior to drug administration

         15. Use of ANY prescription or over the counter medications, within 3 weeks of study drug
             administration, or vitamins or herbal supplements within 2 week of administration of
             the drug administration of study drug (or at least 5 half-lives of the compound
             whichever period is the longer), unless prior approval is granted by both the
             Investigator and Sponsor. Excluded from this list is intermittent use of paracetamol
             at up to 2g/day.

         16. Use moderate or strong inhibitors and/or inducers of cytochrome CYP450 within 4 weeks
             prior to the planned drug administration (or at least 5 half-lives of the compound
             whichever period is the longer)

         17. Subjects have veins unsuitable for intravenous puncture or cannulation on either arm
             (e.g. veins that are difficult to locate, access or puncture veins with a tendency to
             rupture during or after puncture)

         18. Blood liver function tests not in the normal range at screening and on admission

         19. Haemoglobin is less than the lower limit of the reference range at screening and on
             admission.

         20. Donation of more than 500mL blood within 90 days prior to drug administration

         21. Subjects must be non-smokers for at least 3 months prior to screening Note: "Tobacco
             use" includes smoking and the use of snuff and chewing tobacco, and other nicotine or
             nicotine containing products

         22. Any consumption of grapefruit, Seville oranges, wild grapes, black mulberries,
             pomegranates in the form of fruit juice, marmalade or as a raw fruit within 7 days
             prior to dosing of study drug and throughout the study. Any circumstances or
             conditions, which, in the opinion of the investigator may affect full participation in
             the trial or compliance with the protocol

         23. Legal incapacity or limited legal capacity at screening

         24. Vegetarians, vegans or any dietary restrictions conflicting with the study
             standardised menus