Healthy Volunteer Study of the Pharmacokinetics of Oral Piperaquine With OZ439 + TPGS Formulation in the Fasted State

Study Overview
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Brief Summary
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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
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Objectives: To evaluate the piperaquine and OZ439 pharmacokinetics when administered as a combination of piperaquine phosphate tablets with OZ439 / TPGS formulation in the fasted state 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 To determine safety and tolerability of OZ439 and piperaquine phosphate when co-administered.

Official Title
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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

Conditions
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Malaria

Intervention / Treatment
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* Drug: PQP tablets 960mg
* Drug: PQP tablets 1440mg
* Drug: OZ439+TPGS 800mg
* Drug: OZ439 PIB 800mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male/female of any race aged 18-55 years at screening Body Mass Index 18-30kg/m2; body weight >50kg but no more than 100kg at screening Females with negative pregnancy test at screening and admission, non-lactating and of non-child bearing potential confirmed Agree to use acceptable methods of contraception Should not donate egg and sperm from the time of administration of treatment or study medication until 3 months following dose of study medication 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: Male subjects with a female partner(s) who is (are) pregnant or lactating from the time of the administration of study medication Has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion, e.g. gastrectomy, diarrhoea. History of allergic reactions to artemisinin-based compounds, 4-aminoquinolines such as piperaquine or any other clinically relevant allergy to drugs or food. Any clinically relevant history of cow's milk intolerance/allergy. 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. 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 History of post-antibiotic colitis 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 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 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 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 History or clinical evidence of alcohol abuse, or any recreational drug abuse within the 2 years prior to screening Mentally handicapped Participation in a drug trial within 90 days prior to drug administration 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. 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) 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) Blood liver function tests not in the normal range at screening and on admission Haemoglobin is less than the lower limit of the reference range at screening and on admission. Donation of more than 500mL blood within 90 days prior to drug administration 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 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 Legal incapacity or limited legal capacity at screening Vegetarians, vegans or any dietary restrictions conflicting with the study standardised menus

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>PQP tablets 1440mg and OZ439+TPGS 800mg co-administered as a single oral dose fasted. | Drug: PQP tablets 1440mg<br>* Piperaquine phosphate tablets 1440mg<br>Drug: OZ439+TPGS 800mg<br>* OZ439+TPGS prototype formulation 800mg<br>|
| Experimental: Treatment B<br>PQP tablets 960mg and OZ439+TPGS 800mg co-administered as a single oral dose fasted. | Drug: PQP tablets 960mg<br>* Piperaquine phosphate tablets 960mg<br>Drug: OZ439+TPGS 800mg<br>* OZ439+TPGS prototype formulation 800mg<br>|
| Active Comparator: Treatment C - Reference<br>PQP Tablets 1440 mg and OZ439 PIB 800mg + full fat cow's milk | Drug: PQP tablets 1440mg<br>* Piperaquine phosphate tablets 1440mg<br>Drug: OZ439 PIB 800mg<br>* OZ439 Powder in Bottle Aqueous Solution 800mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OZ439 Cmax | OZ439 maximum concentration observed | 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 | 
| OZ439 AUC0-inf | Area under the OZ439 plasma concentration time curve from time zero to time infinity using observed values. | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Piperaquine Cmax | Piperaquine maximum concentration observed | 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 | 
| Piperaquine AUC0-inf | Area under the Piperaquine plasma concentration time curve from time zero to time infinity using observed values. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetics, safety, tolerability, bioavailability