Clinical trial NCT01853475: Healthy Volunteer Study of the Pharmacokinetics of Oral Piperaquine With OZ439 + TPGS Formulation in the Fasted State
Official title: Open Label, Parallel Group Study to Investigate the Pharmacokinetics (PK) Following Oral Co-administration of Piperaquine Phosphate (PQP) Tablets With a Prototype OZ439 + TPGS Formulation in the Fasted State in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malaria
Keywords: pharmacokinetics
safety
tolerability
bioavailability
Lead sponsor: Medicines for Malaria Venture
Sponsor class: OTHER
Collaborators: name: Richmond Pharmacology Limited
First posted: 2013-05-15
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Detailed description: Objectives:

1. To evaluate the piperaquine and OZ439 pharmacokinetics when administered as a combination of piperaquine phosphate tablets with OZ439 / TPGS formulation in the fasted state
2. To evaluate the piperaquine and OZ439 pharmacokinetics of a reference free combination formulation: piperaquine phosphate tablets with OZ439 powder in bottle (PIB) given with full fat milk
3. To determine safety and tolerability of OZ439 and piperaquine phosphate when co-administered.

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

Primary outcomes:
measure: OZ439 Cmax
timeFrame: Day 1 pre-dose and post-dose at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16 and 24 hours(Day 2), and, 48 (Day 3), 72 (Day 4), 96 (Day 5),168 (Day 8), Day 11, Day 15, Day 29 and Day 43
measure: OZ439 AUC0-inf
timeFrame: Day 1 pre-dose and post-dose at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16 and 24 hours(Day 2), and, 48 (Day 3), 72 (Day 4), 96 (Day 5),168 (Day 8), Day 11, Day 15, Day 29 and Day 43
Secondary outcomes:
measure: Piperaquine Cmax
timeFrame: Day 1 pre-dose and post-dose at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16 and 24 hours(Day 2), and, 48 (Day 3), 72 (Day 4), 96 (Day 5),168 (Day 8), Day 11, Day 15, Day 29 and Day 43
measure: Piperaquine AUC0-inf
timeFrame: Day 1 pre-dose and post-dose at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16 and 24 hours(Day 2), and, 48 (Day 3), 72 (Day 4), 96 (Day 5),168 (Day 8), Day 11, Day 15, Day 29 and Day 43
Other outcomes:
Locations:
city: Croyden
country: United Kingdom
facility: Richmond Pharmacology Limited
state: London
Study officials:
affiliation: Richmond Pharmacology Limited
name: Ulrike Lorch, MD FRCA FFPM
role: PRINCIPAL_INVESTIGATOR
References: