Study to Evaluate the Pharmacokinetics of Single and Multiple Doses of Apremilast in Healthy Adult Male Korean Subjects

Study Overview
=================
Brief Summary
-----------------
This two-part study was designed to evaluate the pharmacokinetics (PK) of single and multiple doses of apremilast in healthy adult Korean males.

Detailed Description
-----------------
The study will consist of two parts. Part 1 will evaluate the PK of ascending single doses of apremilast. Part 2 will evaluate the PK of apremilast when administered as multiple doses over 14 days.

Official Title
-----------------
A Phase 1, Open-label, Two Part Study to Evaluate the Pharmacokinetics of Single and Multiple Doses of Apremilast in Healthy Adult Male Korean Subjects

Conditions
-----------------
Pharmacokinetics

Intervention / Treatment
-----------------
* Drug: Apremilast
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: - Subjects must satisfy the following criteria to be enrolled in the study: Healthy adult male Korean subjects between 18 and 45 years of age (inclusive) at the time of signing the informed consent form (ICF). Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted. Subject is willing and able to adhere to the study visit schedule and other protocol requirements. Must be able to communicate with the Investigator and understand and comply with the requirements of the study. Must be in good health as determined by the Investigator according to past medical history, physical examination (PE), vital signs, 12-lead electrocardiogram (ECG), and laboratory tests. Must have a body mass index (BMI) between 18 and 30 kg/m^2 (inclusive). Clinical laboratory tests must be within normal limits or considered by the Investigator to be not clinically significant. Vital signs (systolic and diastolic blood pressure, pulse rate, and oral [or tympanic] body temperature) will be assessed in the supine position after the subject has rested for at least five minutes. Subject must be afebrile (febrile [oral or tympanic] is defined as ≥ 38°C or 100.3°F) with vital signs within the following ranges: Systolic blood pressure: 90 to 140 mm Hg; Diastolic blood pressure: 50 to 90 mm Hg; Pulse rate: 40 to 110 bpm. Must have a normal or clinically acceptable 12-lead ECG. Subjects must have a QTc value ≤ 450 msec. Must have a normal or clinically acceptable physical examination. Contraception Requirements: - Male subjects (including those who have had a vasectomy) who engage in activity in which conception is possible must use barrier contraception (latex or non-latex condoms NOT made out of natural [animal] membrane [for example, polyurethane]) while on Investigational Product (IP) and for at least 28 days after the last dose of investigational product (IP). Must agree to refrain from donating sperm, blood or plasma (other than for this study) while participating in this study, and for at least 28 days after the last dose of IP. Exclusion Criteria: The presence of any of the following will exclude any healthy subject from enrollment into the study: History of any clinically significant and relevant neurological, psychiatric, gastrointestinal, renal, hepatic, cardiovascular, psychological, pulmonary, metabolic, endocrine, hematological, allergic disease, drug allergies, or other major disorders. Any condition which places the subject at unacceptable risk if he were to participate in the study, or confounds the ability to interpret data from the study. Use of any prescribed systemic or topical medication within 30 days of the first dose administration. Use of any non-prescribed systemic or topical medication (including vitamin/mineral supplements, and herbal medicines) within 14 days of the first dose administration. Any surgical or medical condition possibly affecting drug absorption, distribution, metabolism and excretion, eg, bariatric procedure, colon resection, irritable bowel syndrome, Crohn's disease, etc. Subjects with cholecystectomy and appendectomy may be included. Exposure to an investigational drug (new chemical entity) within 30 days prior to the first dose administration or 5 half-lives of that investigational drug, if known (whichever is longer). Donated blood or plasma within eight weeks before the first dose administration to a blood bank or blood donation center. History of drug abuse (as defined by the current version of the Diagnostic and Statistical Manual [DSM]) within 2 years before dosing, or a positive drug screen reflecting consumption of illicit drugs. History of alcohol abuse (as defined by the current version of the DSM) within 2 years before dosing, or a positive alcohol screen. Known to have hepatitis, or known to be a carrier of the hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibodies, or have a positive result to the test for HBsAg, HCV antibodies or human immunodeficiency virus (HIV) antibodies at Screening.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Male

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Part 1 of the study was a 3-treatment period, 3-sequence crossover study. Part 2 was a parallel-group, placebo-controlled, single-period study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Apremilast 20 mg<br>A single oral dose of 20 mg apremilast. | Drug: Apremilast<br>* Tablet for oral administration<br>* Other names: OTEZLA®;|
| Experimental: Part 1: Apremilast 30 mg<br>A single oral dose of 30 mg apremilast. | Drug: Apremilast<br>* Tablet for oral administration<br>* Other names: OTEZLA®;|
| Experimental: Part 1: Apremilast 40 mg<br>A single oral dose of 40 mg apremilast. | Drug: Apremilast<br>* Tablet for oral administration<br>* Other names: OTEZLA®;|
| Experimental: Part 2: Apremilast 30 mg BID<br>30 mg apremilast orally twice a day (BID) for 14 days. | Drug: Apremilast<br>* Tablet for oral administration<br>* Other names: OTEZLA®;|
| Placebo Comparator: Part 2: Placebo<br>Matching placebo orally twice a day for 14 days. | Drug: Placebo<br>* Tablet for oral administration<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Maximum Observed Plasma Concentration (Cmax) of Apremilast | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. | Day 1 of each treatment period at predose (0 hour) and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60, and 72 hours post-dose. | 
| Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of Apremilast |  | Day 1 of each treatment period at predose (0 hour) and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60, and 72 hours post-dose. | 
| Part 1: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) for Apremilast |  | Day 1 of each treatment period at predose (0 hour) and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60, and 72 hours post-dose. | 
| Part 1: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) for Apremilast |  | Day 1 of each treatment period at predose (0 hour) and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60, and 72 hours post-dose. | 
| Part 1: Terminal Elimination Half-life (T1/2) for Apremilast |  | Day 1 of each treatment period at predose (0 hour) and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60, and 72 hours post-dose. | 
| Part 1: Apparent Clearance of Apremilast From Plasma After Extravascular Administration (CL/F) |  | Day 1 of each treatment period at predose (0 hour) and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60, and 72 hours post-dose. | 
| Part 1: Apparent Volume of Distribution of Apremilast During the Terminal Phase (Vz/F) |  | Day 1 of each treatment period at predose (0 hour) and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60, and 72 hours post-dose. | 
| Part 2: Area Under the Plasma Concentration-time Curve During a Dosage Interval (AUCτ) for Apremilast | Area under the plasma concentration-time curve during a dosage interval (tau) at steady state, where tau is 12 hours. | Day 1 and day 14 prior to the morning dose (0 hour), and at 0.5, 1, 1.5, 2, 3, 5, 8, and 12 hours after the morning dose | 
| Part 2: Maximum Observed Plasma Concentration (Cmax) of Apremilast |  | Day 1 and day 14 prior to the morning dose (0 hour), and at 0.5, 1, 1.5, 2, 3, 5, 8, and 12 hours after the morning dose | 
| Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of Apremilast |  | Day 1 and day 14 prior to the morning dose (0 hour), and at 0.5, 1, 1.5, 2, 3, 5, 8, and 12 hours after the morning dose | 
| Part 2: Terminal Elimination Half-life (T1/2) for Apremilast |  | Day 14 prior to the morning dose (0 hour), and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60, and 72 hours after the morning dose | 
| Part 2: Apparent Clearance of Apremilast From Plasma After Extravascular Administration (CL/F) |  | Day 14 prior to the morning dose (0 hour), and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60, and 72 hours after the morning dose | 
| Part 2: Apparent Volume of Distribution of Apremilast During the Terminal Phase (Vz/F) |  | Day 14 prior to the morning dose (0 hour), and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36, 48, 60, and 72 hours after the morning dose | 
| Part 2: Ratio of Accumulation | Ratio of accumulation calculated as Day 14 AUC0-τ / Day 1 AUC0-τ | Day 1 and day 14 prior to the morning dose (0 hour), and at 0.5, 1, 1.5, 2, 3, 5, 8, and 12 hours after the morning dose, and on day 14 only at 24, 36, 48, 60, and 72 hours after the morning dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (AEs) |  | Part 1, up to 40 days; Part 2, up to 24 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Apremilast, Healthy Adult Male, Korean Subjects, Pharmacokinetics