Healthy Volunteers
Conditions
Keywords
OZ439, Bioavailability, Food Effect
Brief summary
This study is designed to assess prototype formulations compared to the aqueous dispersion of Active Pharmaceutical Ingredient used in Phase I and Phase IIa studies to date. It is hoped that the bioavailability of OZ439 can be enhanced in the fasted state to be close to that observed when given after food. This will improve the utility of OZ439 in the field as well as decreasing the cost of treatment (by decreasing the dose of OZ439 required) which is very important for an antimalarial drug product destined for use in developing counties.
Detailed description
This study was a single centre, open-label, pharmacokinetic, randomized cross-over study in healthy male volunteers and post-menopausal women. This study was conducted over three different cohorts as follows: Cohort 1: Subjects received a single 800 mg (as free base) dose of five different treatment regimes (treatments A, B, C, D and E) on five occasions. Cohort 2: Subjects received a single 800 mg (as free base) dose of four different treatment regimes (treatments F, G, H and I) on four occasions. Cohort 3: Subjects received a single dose, 800mg (as free base) of prototype solution formulation 1 (treatment J) and 400mg (as free base) of prototype solution formulation 1 (treatment K) on two occasions. The treatments were administered under the fasted state.
Interventions
DRUGOZ439 mesylate 800mg Powder in Bottle for Oral Suspension
OZ439 800 mg (as free base) as powder in a bottle for reconstitution in a suspension prior to oral administration
DRUGOZ439 mesylate 400mg Prototype Solution Formula 1
OZ439 400 mg (as free base) as a prototype solution formulation 1
DRUGOZ439 mesylate 800mg Prototype Solution Formula 1
OZ439 800 mg (as free base) as a prototype solution formulation 1
DRUGOZ439 mesylate 800mg Prototype Solution Formula 2
OZ439 800 mg (as free base) as a prototype solution formulation 2
Sponsors
Nucleus Network Ltd
Syneos Health
Medicines for Malaria Venture
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male and female volunteers between 18 and 55 years (inclusive). Post-menopausal women with amenorrhoea for at least 2 years are eligible confirmed by FSH level \>/ = 25microlU/ml * Body mass Index between 18 and 30 kg/m2, inclusive; and body weight \> 50 kg. * Healthy as determined by pre-study medical history, physical examination (including body temperature), 12 Lead ECG. * Male volunteers must agree to use a double barrier method of contraception including abstinence, condom plus diaphragm or condom plus IUD or condom plus stable oral/transdermal/injectable hormonal contraceptive by female partner for at least 14 days prior to the time of the first dose of study drug through 90 days after the last dose of study drug and must also agree to not donate sperm for 90 days after the last dose of study drug. Vasectomy with zero sperm count for 6 months minimum prior to the first dose of study drug is an acceptable form of contraception * Clinical laboratory tests at screening within the reference ranges or if outside the normal range not clinically significant. ALT, AST and total bilirubin must be within the normal range * Able and willing to give written informed consent * Willing and able to adhere to the lifestyle guideline requirements * Willing and able to be confined to the Clinical Research Unit as required by the protocol
Exclusion criteria
* Evidence of or history of clinically significant oncologic, pulmonary, hepatic, cardiovascular, hematologic, metabolic, neurological, immunologic, nephrologic, endocrine, psychiatric disease, or current infection * Evidence of or history of clinically significant gastrointestinal (excluding appendectomy and cholecystectomy) disease or current infection. * Any condition that could possibly affect drug absorption, e.g. gastrectomy, diarrhea * History of post-antibiotic colitis * Pregnancy or breastfeeding * QTc greater than 450 msec for males and females as corrected by the Fredricia's formula or evidence or history of abnormal cardiac rhythm * History of drug or alcohol abuse within the past 2 years prior to Screening * Tobacco users (includes stopping smoking less than 90 days prior to screening. Tobacco use includes smoking and the use of snuff and chewing tobacco, and other nicotine containing products * Received an investigational drug or participated in another research study within 30 days of the first dose of study drug in any part of the study * Use of prescription drugs within 14 days prior to the first dose of study drug in Period 1, or need for any antibiotic during the study * Received any non prescription medications, vitamins, herbal supplements or dietary supplements within 7 days of the first dose of study drug in Period 1, unless prior approval is granted. Excluded from this list is intermittent use of acetaminophen at doses of up to 2 g/day * Consumed alcohol within 72 hours of Day -1 in any part of the study, or have a positive alcohol screen at screening or each admission * Consumed fruit juice or ate grapefruit within 7 days prior to the first dose of study drug in any part of the study * Positive test for human immunodeficiency virus, hepatitis B surface antigen or anti-hepatitis C virus * Positive urine drug screen at Screening or admission * History of intolerance or hypersensitivity to artemisinins * Likelihood of requiring treatment during the study period with drugs not permitted by the study protocol * Volunteers who have donated blood or experienced significant blood loss within 90 days of screening * Hemoglobin \< 13.5 g/dL for males and \< 12.5 g/dL for females * Any concern by the investigator regarding the safe participation of the volunteer or any reason the investigator considers the volunteer inappropriate for participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| OZ439 Cmax | 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 and 168 hours post dosing | The maximum observed plasma drug concentrations (Cmax) |
| OZ439 AUC0-∞ | 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 and 168 hours post dosing | Area under the plasma concentration-time curve from zero to infinity (AUC0-∞) |
| OZ439 t1/2 | 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 and 168 hours post dosing | Apparent terminal half life (t1/2) |
Countries
Australia
Participant flow
Recruitment details
The first subject was randomised on 19-Apr-12; The last subject last visit was on 04-Aug-12. Subjects were recruited at the study site, Nucleus Network.
Pre-assignment details
There was no wash-out, run-in or transition period between enrolment and group assignment.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Subjects received a single dose of OZ439 800mg PIB Fed, then OZ439 PIB Fasted, then OZ439 800mg with milk, OZ439 800mg Prototype 1 Fasted, OZ439 800mg Prototype 1 with milk. | 19 |
| Cohort 2 Subjects received a single dose of OZ439 800mg PIB Fasted, then OZ439 800mg with milk, OZ439 800mg Prototype 2 Fasted, OZ439 800mg Prototype 2 with milk. | 17 |
| Cohort 3 Subjects received a 800mg single dose of OZ439 prototype solution formulation 1 fasted and then a 400mg single dose of OZ439 of prototype solution formulation 1 fasted. | 16 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Fifth Intervention (8 Days) | haemoglobin was <13.5 g/dL | 1 | 0 | 0 |
| Fifth Intervention (8 Days) | Withdrawal by Subject | 1 | 0 | 0 |
| Fourth Intervention (8 Days) | Haemoglobin was <13.5 g/dL | 1 | 0 | 0 |
| Fourth Intervention (8 Days) | QTcF was greater than 450 msec | 1 | 0 | 0 |
| Second Intervention (8 Days) | Haemoglobin was <13.5 g/dL | 0 | 1 | 1 |
| Second Intervention (8 Days) | Vomited Study Drug within 30min of admin | 0 | 0 | 1 |
| Third Intervention (8 Days) | Adverse Event | 1 | 0 | 0 |
| Third Intervention (8 Days) | Elevated AST | 0 | 1 | 0 |
| Third Intervention (8 Days) | QTcF was greater than 450 msec | 1 | 0 | 0 |
| Third Intervention (8 Days) | Vomited Study Drug within 30min of admin | 1 | 3 | 0 |
| Third Intervention (8 Days) | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Cohort 3 | Total |
|---|---|---|---|---|
| Age, Continuous | 29.3 years STANDARD_DEVIATION 6.2 | 27.2 years STANDARD_DEVIATION 5.7 | 25.4 years STANDARD_DEVIATION 4.4 | 27.4 years STANDARD_DEVIATION 5.6 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 19 Participants | 17 Participants | 16 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 17 | 5 / 14 | 4 / 15 | 8 / 17 | 9 / 15 | 5 / 13 | 4 / 15 | 12 / 17 | 5 / 13 | 10 / 14 | 4 / 16 |
| serious Total, serious adverse events | 0 / 17 | 0 / 14 | 0 / 15 | 0 / 17 | 0 / 15 | 0 / 13 | 0 / 15 | 0 / 17 | 0 / 13 | 0 / 14 | 0 / 16 |
Outcome results
Primary
OZ439 AUC0-∞
Area under the plasma concentration-time curve from zero to infinity (AUC0-∞)
Time frame: 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 and 168 hours post dosing
Population: Pharmacokinetic Population: all subjects who received study drug, and completed at least one treatment (provided they had adequate OZ439 plasma concentration data) were included in the pharmacokinetic analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Treatment A: OZ439 800mg PIB Fed | OZ439 AUC0-∞ | 29200 ng.h/mL | Geometric Coefficient of Variation 31.2 |
| Cohort 1 - Treatment B: OZ439 800mg PIB Fasted | OZ439 AUC0-∞ | 10700 ng.h/mL | Geometric Coefficient of Variation 52.8 |
| Cohort 1 - Treatment:OZ439 800mg PIB With Milk | OZ439 AUC0-∞ | 24500 ng.h/mL | Geometric Coefficient of Variation 44 |
| Cohort 1 - Treatment D: OZ439 800 mg Prototype F1 Fasted | OZ439 AUC0-∞ | 19000 ng.h/mL | Geometric Coefficient of Variation 39.6 |
| Cohort 1 - Treatment E: OZ439 800mg Prototype F1 With Milk | OZ439 AUC0-∞ | 25800 ng.h/mL | Geometric Coefficient of Variation 26.9 |
| Cohort 2 - Treatment F: OZ439 800 mg PIB Fasted | OZ439 AUC0-∞ | 7460 ng.h/mL | Geometric Coefficient of Variation 34.1 |
| Cohort 2 - Treatment G: OZ439 800mg PIB With Milk | OZ439 AUC0-∞ | 21600 ng.h/mL | Geometric Coefficient of Variation 33 |
| Cohort 2 - Treatment H: OZ439 800 mg Prototype F2 Fasted | OZ439 AUC0-∞ | 11700 ng.h/mL | Geometric Coefficient of Variation 54.9 |
| Cohort 2 - Treatment I: OZ349 800mg Prototype F2 With Milk | OZ439 AUC0-∞ | 22900 ng.h/mL | Geometric Coefficient of Variation 41.9 |
| Cohort 3 - Treatment J: OZ439 800mg Prototype F1 Fasted | OZ439 AUC0-∞ | 13800 ng.h/mL | Geometric Coefficient of Variation 38 |
| Cohort 3 - Treatment K: OZ439 400mg Prototype F1 Fasted | OZ439 AUC0-∞ | 7410 ng.h/mL | Geometric Coefficient of Variation 33.3 |
Primary
OZ439 Cmax
The maximum observed plasma drug concentrations (Cmax)
Time frame: 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 and 168 hours post dosing
Population: Pharmacokinetic Population: all subjects who received study drug, and completed at least one treatment (provided they had adequate OZ439 plasma concentration data) were included in the pharmacokinetic analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Treatment A: OZ439 800mg PIB Fed | OZ439 Cmax | 1910 ng/ml | Geometric Coefficient of Variation 32.9 |
| Cohort 1 - Treatment B: OZ439 800mg PIB Fasted | OZ439 Cmax | 827 ng/ml | Geometric Coefficient of Variation 47.7 |
| Cohort 1 - Treatment:OZ439 800mg PIB With Milk | OZ439 Cmax | 1930 ng/ml | Geometric Coefficient of Variation 27.4 |
| Cohort 1 - Treatment D: OZ439 800 mg Prototype F1 Fasted | OZ439 Cmax | 1440 ng/ml | Geometric Coefficient of Variation 46.2 |
| Cohort 1 - Treatment E: OZ439 800mg Prototype F1 With Milk | OZ439 Cmax | 1830 ng/ml | Geometric Coefficient of Variation 25.9 |
| Cohort 2 - Treatment F: OZ439 800 mg PIB Fasted | OZ439 Cmax | 538 ng/ml | Geometric Coefficient of Variation 33.2 |
| Cohort 2 - Treatment G: OZ439 800mg PIB With Milk | OZ439 Cmax | 1530 ng/ml | Geometric Coefficient of Variation 31.2 |
| Cohort 2 - Treatment H: OZ439 800 mg Prototype F2 Fasted | OZ439 Cmax | 846 ng/ml | Geometric Coefficient of Variation 44.9 |
| Cohort 2 - Treatment I: OZ349 800mg Prototype F2 With Milk | OZ439 Cmax | 1680 ng/ml | Geometric Coefficient of Variation 36.2 |
| Cohort 3 - Treatment J: OZ439 800mg Prototype F1 Fasted | OZ439 Cmax | 1160 ng/ml | Geometric Coefficient of Variation 35.8 |
| Cohort 3 - Treatment K: OZ439 400mg Prototype F1 Fasted | OZ439 Cmax | 719 ng/ml | Geometric Coefficient of Variation 29 |
Primary
OZ439 t1/2
Apparent terminal half life (t1/2)
Time frame: 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 and 168 hours post dosing
Population: Pharmacokinetic Population: all subjects who received study drug, and completed at least one treatment (provided they had adequate OZ439 plasma concentration data) were included in the pharmacokinetic analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - Treatment A: OZ439 800mg PIB Fed | OZ439 t1/2 | 83.5 hours | Geometric Coefficient of Variation 27.8 |
| Cohort 1 - Treatment B: OZ439 800mg PIB Fasted | OZ439 t1/2 | 82.3 hours | Geometric Coefficient of Variation 46.9 |
| Cohort 1 - Treatment:OZ439 800mg PIB With Milk | OZ439 t1/2 | 70.5 hours | Geometric Coefficient of Variation 45.9 |
| Cohort 1 - Treatment D: OZ439 800 mg Prototype F1 Fasted | OZ439 t1/2 | 90.0 hours | Geometric Coefficient of Variation 26 |
| Cohort 1 - Treatment E: OZ439 800mg Prototype F1 With Milk | OZ439 t1/2 | 79.8 hours | Geometric Coefficient of Variation 27.2 |
| Cohort 2 - Treatment F: OZ439 800 mg PIB Fasted | OZ439 t1/2 | 84.7 hours | Geometric Coefficient of Variation 27.3 |
| Cohort 2 - Treatment G: OZ439 800mg PIB With Milk | OZ439 t1/2 | 79.3 hours | Geometric Coefficient of Variation 28 |
| Cohort 2 - Treatment H: OZ439 800 mg Prototype F2 Fasted | OZ439 t1/2 | 85.7 hours | Geometric Coefficient of Variation 22 |
| Cohort 2 - Treatment I: OZ349 800mg Prototype F2 With Milk | OZ439 t1/2 | 70.6 hours | Geometric Coefficient of Variation 17.7 |
| Cohort 3 - Treatment J: OZ439 800mg Prototype F1 Fasted | OZ439 t1/2 | 63.6 hours | Geometric Coefficient of Variation 14.7 |
| Cohort 3 - Treatment K: OZ439 400mg Prototype F1 Fasted | OZ439 t1/2 | 91.1 hours | Geometric Coefficient of Variation 35.7 |