Malaria
Conditions
Brief summary
This study is an open-label, two-part study to determine the absolute bioavailability (BA) of OZ439 using simultaneous intravenous \[14C\]-OZ439 microdose/800mg oral dosing and to investigate the pharmacokinetics (PK) of OZ439 granules administered as single doses suspended in different volumes and when co-administered with a single dose of Cobicistat, a strong CYP3A4 inhibitor, to healthy subjects in fasted state.
Detailed description
Primary objectives of this study are: * to determine the absolute bioavailability of OZ439 following a single oral dose of OZ439 dispersion and a simultaneous single intravenous (iv) microdose (100 μg) infusion of \[14C\]-OZ439 under fasted conditions (Part 1) * To evaluate the effects of a single oral dose of cobicistat, a strong cytochrome P450 (CYP) 3A4 inhibitor, on the pharmacokinetic (PK) profile of a single oral dose of a dispersion of OZ439 simple granules under fasted conditions (Part 2) * To evaluate the PK of single doses of OZ439 granules when restricting the target dosing volumes to 64.5 or 100 mL (Parts 1 and 2) Secondary objectives are: * To assess the safety and tolerability of OZ439 when administered alone, and to assess the safety and tolerability of OZ439 and cobicistat when co-administered as single doses to healthy subjects (Parts 1 and 2) * To determine the PK parameters of OZ439 single iv microdose (100 μg) infusion of \[14C\]-OZ439 (Part 1) * To assess the effects of the total dosing volume and of dose to volume ratio on OZ439 PK under fasted conditions (Parts 1 and 2) * To determine the PK parameters and exposures of cobicistat (Part 2)
Interventions
DRUGSingle oral dose of 800 mg OZ439
Single oral dose of 800 mg OZ439
DRUGSingle oral dose of 400 mg OZ439
Single oral dose of 400 mg OZ439
DRUGSingle oral dose of cobicistat
Single oral dose of 150 mg cobicistat
DRUGiv infusion of [14C]-OZ439
15-minute 10-mL iv infusion of 100 μg \[14C\]-OZ439
Sponsors
Medicines for Malaria Venture
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Part1: Open label, one treatment Part 2: Open-label, randomized, single-dose, 3-way cross-over study
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Body mass index (BMI) : 18.0-30.0 kg/m2, inclusive, at screening * Weight : \>50 kg, at screening * Status : healthy subjects * Female subjects must be of non-childbearing potential (either surgically sterilized or physiologically incapable of becoming pregnant, or post-menopausal \[defined as spontaneous amenorrhoea for at least 1 year or spontaneous amenorrhoea for at least 6 months confirmed by a follicle stimulating hormone (FSH) result indicating a post-menopausal status\]) and have a negative pregnancy test at screening and at (each) admission to the clinical research center. As all female subjects must be of non-childbearing potential, they are not required to use any contraception during this study. * Male subjects must use adequate contraception and not donate sperm from (first) admission to the clinical research center until 90 days after the follow-up visit. Adequate contraception for the male subject (and his female partner) is defined as surgical sterilization (vasectomy), using hormonal contraceptives (implantable, patch, oral, injectable) or an intrauterine device or system combined with at least 1 of the following forms of contraception (barrier method): a diaphragm or cervical cap, or a condom. Also, total abstinence, in accordance with the lifestyle of the subject is acceptable. * Must have QTcF ≤450 ms and QTcB ≤450 ms (male subjects); QTcF ≤470 ms and QTcB ≤470 ms (female subjects), and PR-interval ≤200 ms for screening, and Day -1 and pre-dose ECG measurements of the (first) treatment period * Ability and willingness to abstain from alcohol and methylxanthine-containing beverages or food (coffee, tea, cola, chocolate, energy drinks) from 48 hours prior to (each) admission to the clinical research center * Willing and able to communicate and participate in the whole study * Willing and able to sign the ICF
Exclusion criteria
* A subject who meets any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| OZ439 Fpo | OZ439: Pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168 hours post-dose. [14C]-OZ439: 10, 15, 20, 30 and 45 minutes after start of iv infusion then 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168 hours | OZ439 Absolute oral bioavailability |
| OZ439 Cmax | Pre-dose, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168, 216, 264, 312 hours post-dose | OZ439 maximum concentration observed |
| OZ439 C168h | 168 hours post-dose | OZ439 concentration observed at 168h |
| OZ439 AUC0-168h | Pre-dose, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168 hours post-dose | Area under the OZ439 plasma concentration time curve from time zero to 168h |
| OZ439 AUC0-inf | Pre-dose, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168, 216, 264, 312 hours post-dose | Area under the OZ439 plasma concentration time curve from time zero to infinity |
Countries
Netherlands
Participant flow
Pre-assignment details
Screened volunteers: 48 Screening failures: ECG: 7 Clinical laboratory: 3 Medical history: 2 Vital signs: 1 Physical examination: 1 Other: 1 Approved but not dosed Reserve: 5 Not in clinic/Personal: 2
Participants by arm
| Arm | Count |
|---|---|
| Part 1 open-label study in 8 healthy subjects to determine the absolute bioavailability of OZ439 following a single oral dose of OZ439 and co-administration of a single iv infusion of a \[14C\] OZ439 radiolabeled microdose | 8 |
| Part 2 open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment | 18 |
| Total | 26 |
Baseline characteristics
| Characteristic | Part 1 | Part 2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 18 Participants | 26 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispano or Latino | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 15 Participants | 20 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 8 Participants | 18 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 18 | 0 / 18 | 0 / 18 |
| other Total, other adverse events | 1 / 8 | 10 / 18 | 4 / 18 | 5 / 18 |
| serious Total, serious adverse events | 0 / 8 | 0 / 18 | 0 / 18 | 0 / 18 |
Outcome results
Primary
OZ439 AUC0-168h
Area under the OZ439 plasma concentration time curve from time zero to 168h
Time frame: Pre-dose, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168 hours post-dose
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 | OZ439 AUC0-168h | 9857 ng.h/mL | Geometric Coefficient of Variation 37.3 |
| Part 2, Treatment C: Single Oral Dose of 400 mg OZ439 | OZ439 AUC0-168h | 6049 ng.h/mL | Geometric Coefficient of Variation 51.5 |
| Part 2, Treatment D:Single Oral Dose 400 mg OZ439+Cobicistat | OZ439 AUC0-168h | 13949 ng.h/mL | Geometric Coefficient of Variation 25.6 |
Primary
OZ439 AUC0-inf
Area under the OZ439 plasma concentration time curve from time zero to infinity
Time frame: Pre-dose, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168, 216, 264, 312 hours post-dose
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 | OZ439 AUC0-inf | 10222 ng.h/mL | Geometric Coefficient of Variation 37.4 |
| Part 2, Treatment C: Single Oral Dose of 400 mg OZ439 | OZ439 AUC0-inf | 6378 ng.h/mL | Geometric Coefficient of Variation 52.3 |
| Part 2, Treatment D:Single Oral Dose 400 mg OZ439+Cobicistat | OZ439 AUC0-inf | 14984 ng.h/mL | Geometric Coefficient of Variation 25.7 |
Primary
OZ439 C168h
OZ439 concentration observed at 168h
Time frame: 168 hours post-dose
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 | OZ439 C168h | 3.54 ng/mL | Geometric Coefficient of Variation 65.3 |
| Part 2, Treatment C: Single Oral Dose of 400 mg OZ439 | OZ439 C168h | 2.48 ng/mL | Geometric Coefficient of Variation 83.1 |
| Part 2, Treatment D:Single Oral Dose 400 mg OZ439+Cobicistat | OZ439 C168h | 6.07 ng/mL | Geometric Coefficient of Variation 46.6 |
Primary
OZ439 Cmax
OZ439 maximum concentration observed
Time frame: Pre-dose, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168, 216, 264, 312 hours post-dose
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 | OZ439 Cmax | 949 ng/mL | Geometric Coefficient of Variation 36.1 |
| Part 2, Treatment C: Single Oral Dose of 400 mg OZ439 | OZ439 Cmax | 649 ng/mL | Geometric Coefficient of Variation 40.7 |
| Part 2, Treatment D:Single Oral Dose 400 mg OZ439+Cobicistat | OZ439 Cmax | 966 ng/mL | Geometric Coefficient of Variation 18.3 |
Primary
OZ439 Fpo
OZ439 Absolute oral bioavailability
Time frame: OZ439: Pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168 hours post-dose. [14C]-OZ439: 10, 15, 20, 30 and 45 minutes after start of iv infusion then 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part 1 | OZ439 Fpo | 35 Absolute bioavailability in % |