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

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.

Inclusion criteria

• Healthy males, or females of non-childbearing potential ie surgically sterilised or post-menopausal
• Age 18 to 55 years
• Body mass index of 18 to 30 kg/m2 inclusive
• Total body weight >50 kg
• Healthy as determined by pre-study medical history, physical examination (including body temperature) and 12-lead ECG
• Must have haematology, clinical chemistry and urinalysis results at screening that are within the reference range or ncs
• Must agree to use an adequate method of contraception
• Must demonstrate their ability to swallow an empty size 000 capsule
• Must be willing and able to communicate and participate in the whole study
• Must provide written informed consent

Exclusion criteria

• Evidence or history of clinically significant oncological, pulmonary, chronic respiratory, hepatic, cardiovascular, haematological, metabolic, neurological, immunological, nephrological, endocrine or psychiatric disease, or current infection
• Clinically relevant abnormalities in the ECG (12 standard leads) and/or QTcF >450 ms (males) or >470 ms (females)
• Evidence or history of clinically significant GI disease or surgery (excluding appendectomy or cholecystectomy)
• Any condition that could possibly affect drug absorption, eg gastrectomy or diarrhoea
• History of post-antibiotic colitis
• History of any drug or alcohol abuse in the past 2 years prior to screening
• 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
• Receipt of an investigational drug or participation in another clinical research study within the previous 3 months
• Subjects who are study site employees, or immediate family members of a study site or sponsor employee
• Subjects who have previously been enrolled in this study
• Use of any prescription or non-prescription medications, vitamins, herbal supplements or dietary supplements within 14 days prior to the first dose
• Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab)or human immunodeficiency virus (HIV-1 or HIV-2 antibody) results
• Positive urine drug screen result
• History of intolerance or hypersensitivity to artemisinins
• Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients
• Presence or history of allergy requiring treatment; hayfever is allowed unless it is active
• Donation or loss of >400 mL of blood within the previous 3 months
• Haemoglobin result below the lower limit of the reference range
• Regular alcohol consumption in males >21 units per week and females >14 units per week
• Subjects who do not have suitable veins
• Acute diarrhoea or constipation in the 7 days before the predicted first study day.
• Presence of non-removable metal objects in the abdomen
• Radiation exposure exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years
• Failure to satisfy the investigator of fitness to participate for any other reason