Study to Evaluate Pharmacokinetics, Safety and Tolerability of Dolutegravir and Rilpivirine (JULUCA™) 50 Milligram (mg)/25 mg Tablets in Healthy Subjects of Japanese Descent

ViiV Healthcare16 enrolled

Overview

Dolutegravir (DTG), a human immunodeficiency virus (HIV)-1 integrase inhibitor (INI), and Rilpivirine (RPV), a non-nucleoside HIV-1 reverse transcriptase inhibitor (NNRTI), are each approved in the United States (US), European Union, and other countries for the treatment of HIV-1 infection. JULUCA is a combination of Dolutegravir and Rilpivirine indicated for the treatment of HIV-1 infection in antiretroviral (ARV) experienced adult subjects who are switching from their current antiretroviral treatment to the 2-drug combination. Although, the pharmacokinetics (PK), safety and tolerability of DTG/RPV (50 milligram \[mg\]/25mg) fixed-dose combination (FDC) tablets have been extensively studied, these parameters have not been assessed exclusively in Japanese subjects. This study will evaluate the pharmacokinetics, safety and tolerability of a single dose DTG/RPV 50 mg/25 mg FDC in a healthy adult Japanese population to support a post-approval commitment for DTG/RPV 50 mg/25 mg FDC in Japan.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

HIV Infections

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Subject must be 18 to 55 years of age, at the time of signing the informed consent * Subjects who were born in Japan with 4 ethnic Japanese grandparents. Subjects who have not lived outside Japan for more than 10 years and who are Japanese passport holders (current or expired) * Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring (history and electrocardiogram \[ECG\]) * Subjects with body weight \>=50 kilogram (kg) (110 pounds) for men and \>=45kg (99 pounds) for women and body mass index (BMI) within the range 18.5-31.0 kg per square meter (kg/m\^2) * Male or female subjects; Male subjects with no specific restrictions * A female subject is eligible to participate if she is not pregnant or breastfeeding, and not a woman of childbearing potential (WOCBP) * The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy * Subjects capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol Exclusion Criteria: * Subjects with history of current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention or interfering with the interpretation of data * Subjects with abnormal blood pressure (as determined by the investigator) * Subjects with alanine transaminase (ALT) \>1.5 times upper limit of normal (ULN) * Subjects with bilirubin \>1.5 times ULN (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%) * Subjects with current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) * Subjects with QTcF \>460 millisecond (msec)(Based on the average of the 12-Lead-electrocardiogram (ECG) triplicate readings obtained at Screening) (Note: The QTc is the QT interval corrected for heart rate according to Fridericia's formula (QTcF), and/or another method, machine-read or manually over-read. The specific formula that will be used to determine eligibility and discontinuation for an individual subject should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual subject and then the lowest QTc value used to include or discontinue the subject from the trial) * Subjects with past or intended use of over-the-counter or prescription medication including herbal medications within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to dosing. Acetaminophen, at doses of \<=2 grams per day, is allowed for use any time during the study * Participation in the study would result in loss of blood or blood products in excess of 500 milliliter (mL) within 56 days * Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day * Current enrollment or past participation within the last 30 days before signing of consent in any other clinical study involving an investigational study intervention or any other type of medical research * Subjects with presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to first dose of study intervention * Subjects with positive Hepatitis C antibody test result at screening or within 3 months prior to first dose of study intervention (Note: Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained) * Subjects with positive Hepatitis C RNA test result at screening or within 3 months prior to first dose of study intervention (Note: Test is optional and subjects with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing) * Subjects with positive pre-study drug or alcohol screen * Subjects with positive human immunodeficiency virus (HIV) antibody test * Subjects with regular use of known drugs of abuse * Subjects with creatinine clearance (CrCL) \<60 milliliter per minute * Employment with Janssen, ViiV, GlaxoSmithKline(GSK), or with the Investigator or study site, with direct involvement in the proposed study or other studies under the direction of that Investigator or study site, as well as family members of the employees or the Investigator * Subjects with urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products (e.g. nicotine patches or vaporizing devices) within 6 months prior to screening * Subjects with regular alcohol consumption within 6 months prior to the study defined as: An average weekly intake of \>14 units for males or \>7 units for females. One unit is equivalent to 8 gram of alcohol: a half-pint (approximately 240mL) of beer, 1 glass (125mL) of wine or 1 (25mL) measure of spirits * Subjects with sensitivity to heparin or heparin-induced thrombocytopenia * Subjects with sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study

Outcomes

Primary Outcomes

Area Under the Concentration (AUC) Time Curve From Time Zero Extrapolated to Infinite Time (AUC [0-infinity]) of DTG

Blood samples were collected at indicated time-points for analysis of AUC (0-infinity) of DTG. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

AUC (0-infinity) of RPV

Blood samples were collected at indicated time-points for analysis of AUC (0-infinity) of RPV. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

Area Under the Concentration Time Curve From Time Zero to Last Time of Quantifiable Concentration (AUC [0-t]) of DTG

Blood samples were collected at indicated time-points for analysis of AUC (0-t) of DTG. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

AUC (0-t) of RPV

Blood samples were collected at indicated time-points for analysis of AUC (0-t) of RPV. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

Maximum Observed Plasma Concentration (Cmax) of DTG

Blood samples were collected at indicated time-points for analysis of Cmax of DTG. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

Cmax of RPV

Blood samples were collected at indicated time-points for analysis of Cmax of RPV. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

Absorption Lag Time (Tlag) of DTG

Blood samples were collected at indicated time-points for analysis of tlag of DTG. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

Tlag of RPV

Blood samples were collected at indicated time-points for analysis of tlag of RPV. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

Time to Reach Maximum Observed Concentration (Tmax) of DTG

Blood samples were collected at indicated time-points for analysis of tmax of DTG. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

Tmax of RPV

Blood samples were collected at indicated time-points for analysis of tmax of RPV. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

Time of Last Quantifiable Concentration (Tlast) of DTG

Blood samples were collected at indicated time-points for analysis of tlast of DTG. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

Tlast of RPV

Blood samples were collected at indicated time-points for analysis of tlast of RPV. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

Elimination Half-life (t1/2) of DTG

Blood samples were collected at indicated time-points for analysis of t1/2 of DTG. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

T1/2 of RPV

Blood samples were collected at indicated time-points for analysis of t1/2 of RPV. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

Apparent Elimination Rate Constant (Lambda z) of DTG

Blood samples were collected at indicated time-points for analysis of lambda z of DTG. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

Lambda z of RPV

Blood samples were collected at indicated time-points for analysis of lambda z of RPV. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

Percentage of AUC(0-infinity) That Was Extrapolated (%AUCex) of DTG

Blood samples were collected at indicated time-points for analysis of percentage AUCex of DTG. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

Percentage AUCex of RPV

Blood samples were collected at indicated time-points for analysis of percentage AUCex of RPV. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

Area Under the Plasma Concentration Time Curve From Time Zero to 24 Hours (AUC[0-24]) of DTG

Blood samples were collected at indicated time-points for analysis of AUC(0-24) of DTG. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, and 24 hours post-dose

AUC (0-24) of RPV

Blood samples were collected at indicated time-points for analysis of AUC (0-24) of RPV. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, and 24 hours post-dose

Area Under the Plasma Concentration Time Curve From Time Zero to 72 Hours (AUC[0-72]) of DTG

Blood samples were collected at indicated time-points for analysis of AUC(0-72) of DTG. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, and 72 hours post-dose

AUC (0-72) of RPV

Blood samples were collected at indicated time-points for analysis of AUC (0-72) of RPV. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48 and 72 hours post-dose

Apparent Oral Clearance (CL/F) of DTG

Blood samples were collected at indicated time-points for analysis of CL/F of DTG. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

CL/F of RPV

Blood samples were collected at indicated time-points for analysis of CL/F of RPV. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, 264 hours post-dose

Apparent Oral Volume of Distribution (Vz/F) of DTG

Blood samples were collected at indicated time-points for analysis of Vz/F of DTG. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

Vz/F of RPV

Blood samples were collected at indicated time-points for analysis of Vz/F of RPV. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

Last Quantifiable Concentration (Ct) of DTG

Blood samples were collected at indicated time-points for analysis of Ct of DTG. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, and 120 hours post-dose

Ct of RPV

Blood samples were collected at indicated time-points for analysis of Ct of RPV. PK parameters were calculated by standard non-compartmental analysis.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 16, 24, 48, 72, 120, 168, 216, and 264 hours post-dose

Concentration at 24-hour Post-dose (C24) of DTG

Blood samples were collected at indicated time-points for analysis of C24 of DTG. PK parameters were calculated by standard non-compartmental analysis.

Time frame: At 24 hours post-dose

C24 of RPV

Blood samples were collected at indicated time-points for analysis of C24 of RPV. PK parameters were calculated by standard non-compartmental analysis.

Time frame: At 24 hours post-dose

Secondary Outcomes

Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. A SAE is defined as any untoward medical occurrence that, at any dose: results in death and is life-threatening; which requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent disability or incapacity and birth defect or congenital anomaly, or any other situation that require medical or scientific judgment.

Time frame: Up to Day 18

Change From Baseline in Neutrophil, Lymphocyte, Leukocyte, Monocyte, Eosinophil, Basophil and Platelet Count

Blood samples were collected at indicated time-points for analysis of hematology parameters like platelet count, neutrophils, lymphocytes, leukocyte, monocytes, eosinophils and basophils. Baseline was defined as Day -1. Change from Baseline was defined as post-dose visit value minus Baseline value.