Malaria
Conditions
Keywords
pharmacokinetics, safety, tolerability, bioavailability
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.
Interventions
DRUGPQP tablets 960mg
Piperaquine phosphate tablets 960mg
DRUGPQP tablets 1440mg
Piperaquine phosphate tablets 1440mg
DRUGOZ439+TPGS 800mg
OZ439+TPGS prototype formulation 800mg
DRUGOZ439 PIB 800mg
OZ439 Powder in Bottle Aqueous Solution 800mg
Sponsors
Richmond Pharmacology Limited
Medicines for Malaria Venture
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| OZ439 Cmax | 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 maximum concentration observed |
| OZ439 AUC0-inf | 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 | Area under the OZ439 plasma concentration time curve from time zero to time infinity using observed values. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Piperaquine Cmax | 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 maximum concentration observed |
| Piperaquine AUC0-inf | 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 | Area under the Piperaquine plasma concentration time curve from time zero to time infinity using observed values. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment A: PQP 1440mg & OZ439+TPGS 800mg PQP tablets 1440mg and OZ439+TPGS 800mg co-administered as a single oral dose fasted. | 8 |
| Treatment B: PQP 960mg & OZ439+TPGS 800mg PQP tablets 960mg and OZ439+TPGS 800mg co-administered as a single oral dose fasted. | 8 |
| Treatment C - PQP 1440mg & OZ439 PIB 800mg PQP Tablets 1440 mg and OZ439 PIB 800mg + full fat cow's milk | 8 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Treatment A: PQP 1440mg & OZ439+TPGS 800mg | Treatment B: PQP 960mg & OZ439+TPGS 800mg | Treatment C - PQP 1440mg & OZ439 PIB 800mg | Total |
|---|---|---|---|---|
| Age, Continuous | 33.5 years STANDARD_DEVIATION 13.06 | 30.1 years STANDARD_DEVIATION 6.33 | 30.1 years STANDARD_DEVIATION 5.79 | 31.3 years STANDARD_DEVIATION 8.77 |
| Region of Enrollment United Kingdom | 8 participants | 8 participants | 8 participants | 24 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 7 Participants | 8 Participants | 8 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 8 | 4 / 8 | 5 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
OZ439 AUC0-inf
Area under the OZ439 plasma concentration time curve from time zero to time infinity using observed values.
Time frame: 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
Population: Pharmacokinetic parameters were evaluated using all available concentration data from all 24 subjects who had received at least one treatment of randomised study medication.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: PQP 1440mg & OZ439+TPGS 800mg | OZ439 AUC0-inf | 17500 ng*h/mL | Geometric Coefficient of Variation 27.9 |
| Treatment B: PQP 960mg & OZ439+TPGS 800mg | OZ439 AUC0-inf | 16000 ng*h/mL | Geometric Coefficient of Variation 24.7 |
| Treatment C - PQP 1440mg & OZ439 PIB 800mg | OZ439 AUC0-inf | 18600 ng*h/mL | Geometric Coefficient of Variation 45.4 |
Primary
OZ439 Cmax
OZ439 maximum concentration observed
Time frame: 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
Population: Pharmacokinetic parameters were evaluated using all available concentration data from all 24 subjects who had received at least one treatment of randomised study medication.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: PQP 1440mg & OZ439+TPGS 800mg | OZ439 Cmax | 1540 ng/mL | Geometric Coefficient of Variation 26 |
| Treatment B: PQP 960mg & OZ439+TPGS 800mg | OZ439 Cmax | 1360 ng/mL | Geometric Coefficient of Variation 33.8 |
| Treatment C - PQP 1440mg & OZ439 PIB 800mg | OZ439 Cmax | 1610 ng/mL | Geometric Coefficient of Variation 37.2 |
Secondary
Piperaquine AUC0-inf
Area under the Piperaquine plasma concentration time curve from time zero to time infinity using observed values.
Time frame: 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
Population: Pharmacokinetic parameters were evaluated using all available concentration data from all 24 subjects who had received at least one treatment of randomised study medication.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: PQP 1440mg & OZ439+TPGS 800mg | Piperaquine AUC0-inf | 17200 ng*h/mL | Geometric Coefficient of Variation 29.5 |
| Treatment B: PQP 960mg & OZ439+TPGS 800mg | Piperaquine AUC0-inf | 13400 ng*h/mL | Geometric Coefficient of Variation 23.1 |
| Treatment C - PQP 1440mg & OZ439 PIB 800mg | Piperaquine AUC0-inf | 29700 ng*h/mL | Geometric Coefficient of Variation 48 |
Secondary
Piperaquine Cmax
Piperaquine maximum concentration observed
Time frame: 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
Population: Pharmacokinetic parameters were evaluated using all available concentration data from all 24 subjects who had received at least one treatment of randomised study medication.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: PQP 1440mg & OZ439+TPGS 800mg | Piperaquine Cmax | 202 ng/mL | Geometric Coefficient of Variation 37.6 |
| Treatment B: PQP 960mg & OZ439+TPGS 800mg | Piperaquine Cmax | 122 ng/mL | Geometric Coefficient of Variation 42.1 |
| Treatment C - PQP 1440mg & OZ439 PIB 800mg | Piperaquine Cmax | 630 ng/mL | Geometric Coefficient of Variation 54.4 |