Healthy Volunteers
Conditions
Keywords
Bioavailability
Brief summary
The purpose of this study is to determine the bioavailability of nanoparticulate OZ439 delivered to the proximal small bowel (PSB) via the Enterion™ capsule relative to oral OZ439 suspension (current powder in bottle \[PIB\]) and oral nanoparticulate OZ439. The study will also characterise the plasma concentration time profile of OZ439 when delivered via Enterion capsule to the PSB in comparison with OZ439 PIB formulation delivered orally and nanoparticulate OZ439 delivered orally Safety and tolerability of OZ439 formulations will be determined following delivery to the PSB and administered orally
Detailed description
Previous clinical studies with OZ439 have shown variable PK and a food effect. One hypothesis is that this may be related to a 'common ion effect' leading to precipitation of the drug as a less soluble hydrochloride salt in the stomach, resulting in variable absorption of the drug. This study is designed to investigate the possibility of improving the PK profile by delivering the drug directly to the PSB, thereby bypassing the stomach. The study will compare a previously dosed PIB formulation with oral delivery of a nanoparticulate as a caplet formulation. The same caplet formulation containing nanoparticulate will be administered to the PSB via the Enterion capsule.
Interventions
DRUGOZ439 120mg PIB
120mg dose (as free base) of OZ439 as a solution made up from powder in bottle (PIB)
DRUG120 mg OZ439 caplet
120 mg (as free base) of OZ439 immediate-release (IR) caplet formulation containing nanoparticulate, administered directly via the oral route
DRUG120mg OZ439 caplet via Enterion capsule
120 mg OZ439 (as free base) in an immediate release (IR) caplet formulation containing nanoparticulate,administered orally via the Enterion capsule and delivered directly to the proximal small bowel (PSB)
Sponsors
Medicines for Malaria Venture
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy males, or females of non-childbearing potential ie surgically sterilised or post-menopausal 2. Age 18 to 55 years 3. Body mass index of 18 to 30 kg/m2 inclusive 4. Total body weight \>50 kg 5. Healthy as determined by pre-study medical history, physical examination (including body temperature) and 12-lead ECG 6. Must have haematology, clinical chemistry and urinalysis results at screening that are within the reference range or ncs 7. Must agree to use an adequate method of contraception 8. Must demonstrate their ability to swallow an empty size 000 capsule 9. Must be willing and able to communicate and participate in the whole study 10. Must provide written informed consent
Exclusion criteria
1. Evidence or history of clinically significant oncological, pulmonary, chronic respiratory, hepatic, cardiovascular, haematological, metabolic, neurological, immunological, nephrological, endocrine or psychiatric disease, or current infection 2. Clinically relevant abnormalities in the ECG (12 standard leads) and/or QTcF \>450 ms (males) or \>470 ms (females) 3. Evidence or history of clinically significant GI disease or surgery (excluding appendectomy or cholecystectomy) 4. Any condition that could possibly affect drug absorption, eg gastrectomy or diarrhoea 5. History of post-antibiotic colitis 6. History of any drug or alcohol abuse in the past 2 years prior to screening 7. Subjects who have a breath carbon monoxide reading of greater than 10 ppm at screening. Subjects who are tobacco users (including smokers and users of snuff, chewing tobacco and other nicotine or nicotine-containing products) must have stopped use within 90 days before screening 8. Receipt of an investigational drug or participation in another clinical research study within the previous 3 months 9. Subjects who are study site employees, or immediate family members of a study site or sponsor employee 10. Subjects who have previously been enrolled in this study 11. Use of any prescription or non-prescription medications, vitamins, herbal supplements or dietary supplements within 14 days prior to the first dose 12. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab)or human immunodeficiency virus (HIV-1 or HIV-2 antibody) results 13. Positive urine drug screen result 14. History of intolerance or hypersensitivity to artemisinins 15. Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients 16. Presence or history of allergy requiring treatment; hayfever is allowed unless it is active 17. Donation or loss of \>400 mL of blood within the previous 3 months 18. Haemoglobin result below the lower limit of the reference range 19. Regular alcohol consumption in males \>21 units per week and females \>14 units per week 20. Subjects who do not have suitable veins 21. Acute diarrhoea or constipation in the 7 days before the predicted first study day. 22. Presence of non-removable metal objects in the abdomen 23. Radiation exposure exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years 24. Failure to satisfy the investigator of fitness to participate for any other reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| OZ439 AUC0-∞ | pre dose, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post dose | Area under the plasma concentration-time curve from zero to infinity (AUC0-∞) |
| OZ439 Cmax | pre dose, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post dose | The maximum observed plasma drug concentrations (Cmax) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| OZ439 Tmax | pre dose, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post dose | Time of maximum observed plasma drug concentrations (Tmax) |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sequence 1 Subjects received a single dose of 120 mg OZ439 PIB oral suspension (Regimen A), then 120 mg OZ439 IR caplet (Regimen B); then 120 mg OZ439 caplet formulation containing nanoparticulate delivered to the PSB via Enterion capsule (Regimen C) | 4 |
| Sequence 2 Subjects received a single dose of 120 mg OZ439 IR caplet (Regimen B); then 120 mg OZ439 caplet formulation containing nanoparticulate delivered to the PSB via Enterion capsule (Regimen C); then 120 mg OZ439 PIB oral suspension (Regimen A) | 3 |
| Sequence 3 Subjects received a single dose of 120 mg OZ439 caplet formulation containing nanoparticulate delivered to the PSB via Enterion capsule (Regimen C); then 120 mg OZ439 PIB oral suspension (Regimen A); then 120 mg OZ439 IR caplet (Regimen B). | 4 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| First Intervention (7 Days) | Adverse Event | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Sequence 1 | Sequence 2 | Sequence 3 | Total |
|---|---|---|---|---|
| Age, Continuous | 41.5 years STANDARD_DEVIATION 12 | 35.3 years STANDARD_DEVIATION 14.6 | 36.8 years STANDARD_DEVIATION 12.3 | 38.1 years STANDARD_DEVIATION 11.8 |
| Body Mass Index | 26.50 kg/m^2 STANDARD_DEVIATION 3.7 | 24.67 kg/m^2 STANDARD_DEVIATION 0.58 | 26.75 kg/m^2 STANDARD_DEVIATION 1.89 | 26.09 kg/m^2 STANDARD_DEVIATION 2.47 |
| Region of Enrollment United Kingdom | 4 participants | 3 participants | 4 participants | 11 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 4 Participants | 9 Participants |
| weight | 82.53 kg STANDARD_DEVIATION 13.44 | 68 kg STANDARD_DEVIATION 8.86 | 80.83 kg STANDARD_DEVIATION 1.44 | 77.95 kg STANDARD_DEVIATION 10.58 |
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 | 2 / 10 | 2 / 11 | 3 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 11 | 0 / 10 |
Outcome results
Primary
OZ439 AUC0-∞
Area under the plasma concentration-time curve from zero to infinity (AUC0-∞)
Time frame: pre dose, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post dose
Population: PK population included all subjects who received at least 1 dose of IMP and who had sufficient plasma concentration data for PK parameter estimation.~In addition, for Regimen C only subjects in whom the activation was performed successfully at the target site were included for this regimen.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen A - OZ439 120mg PIB | OZ439 AUC0-∞ | 1230 ng*h/mL | Geometric Coefficient of Variation 46.5 |
| Regimen B - 120 mg OZ439 IR Caplet | OZ439 AUC0-∞ | 907 ng*h/mL | Geometric Coefficient of Variation 46.3 |
| Regimen C - 120 mg OZ439 Caplet Via Enterion Capsule | OZ439 AUC0-∞ | 398 ng*h/mL | Geometric Coefficient of Variation 99 |
Primary
OZ439 Cmax
The maximum observed plasma drug concentrations (Cmax)
Time frame: pre dose, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post dose
Population: PK population included all subjects who received at least 1 dose of IMP and who had sufficient plasma concentration data for PK parameter estimation.~In addition, for Regimen C only subjects in whom the activation was performed successfully at the target site were included for this regimen.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen A - OZ439 120mg PIB | OZ439 Cmax | 180 ng/mL | Geometric Coefficient of Variation 50.5 |
| Regimen B - 120 mg OZ439 IR Caplet | OZ439 Cmax | 82.7 ng/mL | Geometric Coefficient of Variation 73.5 |
| Regimen C - 120 mg OZ439 Caplet Via Enterion Capsule | OZ439 Cmax | 35.4 ng/mL | Geometric Coefficient of Variation 98.7 |
Secondary
OZ439 Tmax
Time of maximum observed plasma drug concentrations (Tmax)
Time frame: pre dose, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post dose
Population: PK population included all subjects who received at least 1 dose of IMP and who had sufficient plasma concentration data for PK parameter estimation.~In addition, for Regimen C only subjects in whom the activation was performed successfully at the target site were included for this regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regimen A - OZ439 120mg PIB | OZ439 Tmax | 2 hours |
| Regimen B - 120 mg OZ439 IR Caplet | OZ439 Tmax | 4 hours |
| Regimen C - 120 mg OZ439 Caplet Via Enterion Capsule | OZ439 Tmax | 4 hours |