Study to Determine the Intra-subject Variability of Pharmacokinetics of Lomitapide in Healthy Subjects

Study Overview
=================
Brief Summary
-----------------
Objectives: To evaluate the intra-subject variability of the pharmacokinetics (PK) of single oral capsule doses of 20 mg lomitapide.

Detailed Description
-----------------
This study will be a single centre, open-label study. It will comprise of 2 single oral doses with at least a 14-day washout between doses. Following the first dose subjects will be discharged from the unit for the remainder of the washout period. Subjects will be re-admitted to the unit on Day -1 (Period 2) and following an overnight fast they will be administered the second dose on Day 1 (Period 2). Subjects will be discharged from the unit following the 168 h PK blood draw.

Official Title
-----------------
A Phase 1, Open-label, Crossover Study to Determine the Intra-subject Variability of the Pharmacokinetics of Single Oral CapsuleDose of 20 mg Lomitapide in Healthy Subjects

Conditions
-----------------
Intra-subject Variability of Pharmacokinetics

Intervention / Treatment
-----------------
* Drug: lomitapide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject is a non-smoking healthy male or female, aged between 18 and 40 years of age. Subject has a BMI of 18.5 - 25 kg/m2. Subject has total body weight between > 50 kg to ≤ 100 kg. Subjects must agree to use acceptable methods of contraception. All females, regardless of childbearing potential, must have a negative serum beta human chorionic gonadotropin pregnancy test at Screening and on admission. In good health, determined by no clinically significant or relevant abnormalities identified by a detailed medical history & full physical examination. No known history of hypersensitivity or previous intolerance to lomitapide. Subjects must be capable of understanding and complying with the requirements of the protocol and must have signed the informed consent form prior to undergoing any study-related procedures. Exclusion Criteria: Subject has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion. History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs. Any clinically significant abnormal laboratory, vital signs or other safety findings as determined by medical history, physical examination or other evaluations. History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator; Electrocardiogram (ECG) abnormalities in the standard 12-lead ECG (at screening) such as a QTcF interval of >450 msec, a history of a prolonged QTc interval or Brugada syndrome. History or current evidence of any clinically relevant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, haematological, endocrinological, allergic, dermatological, metabolic, neurological, psychiatric or other disease. History or laboratory evidence of Gilbert's syndrome. Positive results in any of the serology tests for Hepatitis B Surface Antigen (HbsAg), anti-Hepatitis core antibody (anti-HBc Ig G [and anti-HBc IgM if IgG is positive], Hepatitis C antibodies (anti-HCV), and HIV 1 and 2 antibodies, (anti-HIV 1/2). Use of any drugs of abuse within 6 months prior to admission. Confirmed positive results from urine drug screen (amphetamines, benzodiazepines, cocaine, cannabinoids, opiates, barbiturates and methadone) or from the alcohol breath test at screening and on admission (Day -1). History or clinical evidence of alcohol or drug abuse within one year prior to admission. Mentally handicapped. Participation in a drug trial within 90 days prior to first drug administration. Use of any prescription medication within 2 weeks prior to admission (Day -1), with the exception of the oral contraceptive pill. Use of any substance inducing or inhibiting CYP3A4 enzymes within 30 days prior to admission (Day -1). Use of any over-the-counter (OTC) medication (including vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations) within 7 days prior to admission (Day -1), unless deemed acceptable by the Investigator and Sponsor. Use of alcohol-, grapefruit-, starfruit-, or caffeine-containing foods or beverages within 72 hours prior to admission and through Study Completion. Donation of more than 500 mL of blood within 90 days prior to drug administration. Receipt of blood products within 2 months prior to admission. Poor peripheral venous access. Use of any tobacco- or nicotine-containing products within 6 months prior to admission (Day -1). Any acute or chronic condition, scheduled hospitalisation (inclusive of elective surgery during study), or scheduled travel prior to completion of all study procedures. Any circumstances or conditions, which, in the opinion of the PI, may affect full participation in the trial or compliance with the protocol. Legal incapacity or limited legal capacity at screening. Subjects who are vegetarians, vegans or have any dietary restrictions conflicting with the study standardised menus.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: lomitapide<br>It will comprise of 2 single oral doses with at least a 14-day washout between doses. | Drug: lomitapide<br>* 20 mg dose<br>* Other names: Juxtapid;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | Maximum observed concentration of lomitapide and its metabolites, M1 & M3. | Pre dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours post dose. | 
| Tmax | Time to reach maximum plasma concentration | Pre dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours post dose. | 
| AUC0-t | Area under the concentration-time curve from hour 0 to the last measurable concentration of lomitapide and its metabolites, M1 & M3. | Pre dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours post dose. | 
| AUC0-∞ | Area under the concentration-time curve extrapolated to infinity for lomitapide and its metabolites, M1 & M3. | Pre dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours post dose. | 
| λz | Elimination rate constant estimated from individual linear regression of the terminal part of the log concentration vs time curve | Pre dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours post dose. | 
| t1/2 | Apparent terminal elimination half-life | Pre dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours post dose. |