A Comparison of the Bioavailability of OZ439 When Delivered Directly to the Small Intestine, or Via the Oral Route

Three Way Randomised CrossOver Study in Healthy Subjects to Compare the Relative Bioavailability of Nanoparticulate OZ439 Delivered Via the Enterion™ Capsule to the Proximal Small Bowel With Orally Administered OZ439 as PIB Suspension and Orally Administered Nanoparticulate

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

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: OZ439 120mg PIB; Drug: 120 mg OZ439 caplet; Drug: 120mg OZ439 caplet via Enterion capsule

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.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Nottingham, United Kingdom, NG11 6JS
    • Quotient Clinical

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Regimen A - 120mg OZ439 PIB; 120mg single dose of OZ439 as powder in bottle (PIB) formulation	Drug: OZ439 120mg PIB; 120mg dose (as free base) of OZ439 as a solution made up from powder in bottle (PIB); Other Names: Regimen A
Experimental: Regimen B - 120 mg OZ439 IR caplet; 120 mg single dose of OZ439 immediate release (IR) caplet formulation containing nanoparticulate, administered directly via the oral route	Drug: 120 mg OZ439 caplet; 120 mg (as free base) of OZ439 immediate-release (IR) caplet formulation containing nanoparticulate, administered directly via the oral route; Other Names: Regimen B
Experimental: Regimen C - 120 mg OZ439 caplet via Enterion capsule; 120 mg single dose of OZ439 caplet formulation containing nanoparticulate, administered orally via the Enterion capsule and delivered to the proximal small bowel	Drug: 120mg 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); Other Names: Regimen C

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OZ439 AUC0-∞	Area under the plasma concentration-time curve from zero to infinity (AUC0-∞)	pre dose, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post dose
OZ439 Cmax	The maximum observed plasma drug concentrations (Cmax)	pre dose, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OZ439 Tmax	Time of maximum observed plasma drug concentrations (Tmax)	pre dose, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post dose

Collaborators and Investigators

• Sponsor: Medicines for Malaria Venture
• Investigators: Study Director: Fiona Macintyre, PhD, Medicines for Malaria Venture

Publications and helpful links

Helpful Links

• Company website

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: October 22, 2012
• First Submitted That Met QC Criteria: November 19, 2012
• First Posted (Estimate): November 26, 2012

Study Record Updates

• Last Update Posted (Estimate): March 6, 2015
• Last Update Submitted That Met QC Criteria: February 17, 2015
• Last Verified: February 1, 2015

More Information

Terms related to this study

• Keywords: Bioavailability
• Additional Relevant MeSH Terms: Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Artefenomel
• Other Study ID Numbers: MMV_OZ439_12_003