Drug-drug Interaction (DDI) Study of GSK3640254 With Darunavir/Ritonavir (DRV/RTV) and Etravirine (ETR)

Phase 1

Completed

Conditions: HIV Infections

Interventions: Drug: GSK3640254
Drug: Darunavir/Ritonavir (DRV/RTV)
Drug: Etravirine (ETR)

Registration Number: NCT04630002

Lead Sponsor: ViiV Healthcare

Brief Summary: This is an open-label, single-sequence, multiple-dose, 3 cohort study to investigate the effects of DRV/RTV and/or ETR on the pharmacokinetics (PK) of GSK3640254 and the effects of GSK3640254 on the PK of DRV/RTV and/or ETR. This study will aid in understanding these interactions and resulting changes in exposure (if any) when given in combination with GSK3640254.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 54

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 1: GSK3640254 then DRV/RTV then GSK3640254 + DRV/RTV	GSK3640254	Cohort 1 will include 3 periods. In Period 1 GSK3640254 will be administered (Treatment A). In Period 2 DRV/RTV will be administered (Treatment B). In Period 3 GSK3640254 (Treatment A) and DRV/RTV (Treatment B) will be administered.
Cohort 1: GSK3640254 then DRV/RTV then GSK3640254 + DRV/RTV	Darunavir/Ritonavir (DRV/RTV)	Cohort 1 will include 3 periods. In Period 1 GSK3640254 will be administered (Treatment A). In Period 2 DRV/RTV will be administered (Treatment B). In Period 3 GSK3640254 (Treatment A) and DRV/RTV (Treatment B) will be administered.
Cohort 2: GSK3640254 then ETR then GSK3640254 + ETR	GSK3640254	Cohort 2 will include 3 periods. In Period 1 GSK3640254 will be given (Treatment A). In Period 2 ETR will be given (Treatment C). In Period 3 GSK3640254 (Treatment A) and ETR (Treatment C) will be administered.
Cohort 2: GSK3640254 then ETR then GSK3640254 + ETR	Etravirine (ETR)	Cohort 2 will include 3 periods. In Period 1 GSK3640254 will be given (Treatment A). In Period 2 ETR will be given (Treatment C). In Period 3 GSK3640254 (Treatment A) and ETR (Treatment C) will be administered.
Cohort 3: GSK3640254 then GSK3640254 + DRV/RTV + ETR	Darunavir/Ritonavir (DRV/RTV)	Cohort 3 will include 2 periods. In Period 1 GSK3640254 will be administered (Treatment A). In Period 2 GSK3640254 (Treatment A), DRV/RTV (Treatment B), and ETR (Treatment C) will be administered.
Cohort 3: GSK3640254 then GSK3640254 + DRV/RTV + ETR	Etravirine (ETR)	Cohort 3 will include 2 periods. In Period 1 GSK3640254 will be administered (Treatment A). In Period 2 GSK3640254 (Treatment A), DRV/RTV (Treatment B), and ETR (Treatment C) will be administered.
Cohort 3: GSK3640254 then GSK3640254 + DRV/RTV + ETR	GSK3640254	Cohort 3 will include 2 periods. In Period 1 GSK3640254 will be administered (Treatment A). In Period 2 GSK3640254 (Treatment A), DRV/RTV (Treatment B), and ETR (Treatment C) will be administered.

Primary Outcome Measures

Name	Time	Method
Cohort 1: Cmax of RTV	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 1: Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval at Steady State (AUC[0-tau]) of GSK3640254	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 1: Cmax of DRV	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 2: AUC(0-tau) of GSK3640254	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 2: Cmax of GSK3640254	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 2: AUC(0-tau) of ETR	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 3: AUC(0-tau) of GSK3640254	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 2	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 3: Cmax of GSK3640254	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 2	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 1: Maximum Observed Concentration (Cmax) of GSK3640254	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 1: AUC(0-tau) of DRV	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 1: AUC(0-tau) of RTV	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 2: Cmax of ETR	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

Secondary Outcome Measures

Name	Time	Method
Cohort 2: Ctau of GSK3640254	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 2: Tmax of GSK3640254	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 1: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)	Up to Day 35	An adverse event (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. An SAE is defined as any untoward medical occurrence that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other situations as per medical or scientific judgment. Adverse events which were not Serious were considered as Non-Serious adverse events.
Cohort 2: Number of Participants With SAEs and Non-SAEs	Up to Day 36	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. An SAE is defined as any untoward medical occurrence that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other situations as per medical or scientific judgment. Adverse events which were not Serious were considered as Non-Serious adverse events.
Cohort 1: Plasma Concentration at the End of the Dosing Interval (Ctau) of DRV	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 1: Time of Maximum Observed Concentration (Tmax) of DRV	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 1: Ctau of RTV	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 1: Tmax of RTV	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 1: Ctau of GSK3640254	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 1: Tmax of GSK3640254	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours, 16 Hours, 24 Hours post-dose in Treatment Periods 1 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 2: Ctau of ETR	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 2: Tmax of ETR	Pre-dose and 0.5 Hours, 1 Hour, 1.5 Hours, 2 Hours, 3 Hours, 4 Hours, 6 Hours, 8 Hours, 12 Hours post-dose in Treatment Periods 2 and 3	Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Cohort 3: Number of Participants With SAEs and Non-SAEs	Up to Day 26	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. An SAE is defined as any untoward medical occurrence that, at any dose that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other situations as per medical or scientific judgment. Adverse events which were not Serious were considered as Non-Serious adverse events.
Cohort 1: Number of Participants With AEs Leading to Discontinuations and Deaths	Up to Day 35	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. Number of participants with AEs leading to discontinuations and deaths were reported.
Cohort 2: Number of Participants With AEs Leading to Discontinuations and Deaths	Up to Day 36	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. Number of participants with AEs leading to discontinuations and deaths were reported.
Cohort 3: Number of Participants With AEs Leading to Discontinuations and Deaths	Up to Day 26	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. Number of participants with AEs leading to discontinuations and deaths were reported.
Cohort 1: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Hematology Parameters	Baseline (Pre-dose, Day-1) and up to Day 35	Blood samples were collected for analysis of hematology parameters. Laboratory abnormalities were graded according to Division of Acquired Immunodeficiency Syndrome (DAIDS) grading table Version 2.1. For Hemoglobin Low, Grade 3: 7.0 to \<9.0 Grams per deciliter (g/dL) (males) and 6.5 to \<8.5 g/dL (females),Grade 4: \<7.0 g/dL (males) and \<6.5 g/dL (females); Leukocytes Low, Grade 3: 1000 to 1499 cells per cubic millimeter (cells/mm\^3),Grade 4: \<1000 cells/mm\^3; Lymphocytes Low, Grade 3: 350 to \<500 cells per liter (cells/L),Grade 4: \<350 cells/L; Neutrophils Low, Grade 3: 400 to 599 cells/mm\^3, Grade 4: \<400 cells/mm\^3; Platelets Low, Grade 3: 25,000 to \<50,000 cells/mm\^3, Grade 4: \<25,000 cells/mm\^3. Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.
Cohort 2: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Hematology Parameters	Baseline (Pre-dose, Day-1) and up to Day 36	Blood samples were collected for analysis of hematology parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Hemoglobin Low, Grade 3: 7.0 to \<9.0 g/dL (males) and 6.5 to \<8.5 g/dL (females),Grade 4: \<7.0 g/dL (males) and \<6.5 g/dL (females); Leukocytes Low, Grade 3: 1000 to 1499 cells/mm\^3,Grade 4: \<1000 cells/mm\^3; Lymphocytes Low, Grade 3: 350 to \<500 cells/L,Grade 4: \<350 cells/L; Neutrophils Low, Grade 3: 400 to 599 cells/mm\^3, Grade 4: \<400 cells/mm\^3; Platelets Low, Grade 3: 25,000 to \<50,000 cells/mm\^3, Grade 4: \<25,000 cells/mm\^3. Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.
Cohort 3: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Hematology Parameters	Baseline (Pre-dose, Day-1) and up to Day 26	Blood samples were collected for analysis of hematology parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Hemoglobin Low, Grade 3: 7.0 to \<9.0 g/dL (males) and 6.5 to \<8.5 g/dL (females),Grade 4: \<7.0 g/dL (males) and \<6.5 g/dL (females); Leukocytes Low, Grade 3: 1000 to 1499 cells/mm\^3,Grade 4: \<1000 cells/mm\^3; Lymphocytes Low, Grade 3: 350 to \<500 cells/L,Grade 4: \<350 cells/L; Neutrophils Low, Grade 3: 400 to 599 cells/mm\^3, Grade 4: \<400 cells/mm\^3; Platelets Low, Grade 3: 25,000 to \<50,000 cells/mm\^3, Grade 4: \<25,000 cells/mm\^3. Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.
Cohort 1: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters: Alanine Aminotransferase, Albumin, Alkaline Phosphatase, Amylase, Aspartate Aminotransferase, Bilirubin and Direct Bilirubin	Baseline (Pre-dose, Day-1) and up to Day 35	Blood samples were collected for analysis of clinical chemistry parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Alanine Aminotransferase High; Grade 3: 5.0 to \<10.0 times (×) Upper Limit Normal (ULN), Grade 4: \>=10.0 × ULN; Albumin Low, Grade 3: \<2.0 grams per deciliter (g/dL), Grade 4: Not Applicable; Alkaline Phosphatase High, Grade 3: 5.0 to \<10.0 × ULN, Grade 4: \>=10.0 × ULN; Amylase High, Grade 3: 3.0 to \<5.0 × ULN, Grade 4: \>=5.0 × ULN; Aspartate Aminotransferase High, Grade 3: 5.0 to \<10.0 × ULN, Grade 4: \>=10.0 × ULN; Bilirubin High, Grade 3: 2.6 to\<5.0 × ULN, Grade 4: \>=5.0 × ULN and Direct Bilirubin High, Grade 3: \>ULN with other signs and symptoms of hepatotoxicity, Grade 4: \>ULN with life-threatening consequences. Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.
Cohort 1: Number of Participants With Vital Sign Values of Potential Clinical Importance (PCI) Criteria	Up to Day 35	Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate were measured in a supine position after atleast 5 minutes of rest. The PCI ranges for vitals were as follows; for SBP \<85 or \>140 millimeters of mercury (mmHg), for DBP \<45 or \>90 mmHg, for pulse rate \<40 or \>100 beats per minute. The number of participants with vital signs of PCI were presented.
Cohort 2: Number of Participants With Vital Sign Values of PCI Criteria	Up to Day 36	Vital signs including SBP, DBP and pulse rate were measured in a supine position after atleast 5 minutes of rest. The PCI ranges for vitals were as follows; for SBP \<85 or \>140 mmHg, for DBP \<45 or \>90 mmHg, for pulse rate \<40 or \>100 beats per minute. The number of participants with vital signs of PCI were presented.
Cohort 1: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters: Calcium, Creatine Kinase, Creatinine, Phosphate, Potassium and Sodium	Baseline (Pre-dose, Day-1) and up to Day 35	Blood samples were collected for analysis of clinical chemistry parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Calcium High, Grade 3: 12.5 to \<13.5 milligrams/deciliter (mg/dL), Grade 4: \>=13.5 mg/dL; Calcium Low, Grade 3: 6.1 to \<7.0 mg/dL, Grade 4: \<6.1 mg/dL; Creatine Kinase High, Grade 3: 10 to \<20 × ULN, Grade 4: \>=20 × ULN; Creatinine High, Grade 3: \>1.8 to \<3.5 ULN, Grade 4: \>=3.5 × ULN; Phosphate Low, Grade 3: 1.0 to \<1.4 mg/dL, Grade 4: \<1.0 mg/dL; Potassium High, Grade 3: 6.5 to \<7.0 Milliequivalents per liter (mEq/L),Grade 4: \>=7.0 mEq/L; Potassium Low, Grade 3: 2.0 to \<2.5 mEq/L, Grade 4: \<2.00 mEq/L; Sodium High, Grade 3: 154 to \<160 mEq/L, Grade 4:\>=160 mEq/L; Sodium Low, Grade 3: 121 to \<125 mEq/L, Grade 4:\<=120 mEq/L. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.
Cohort 1: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters: Glucose, Triglycerides, Lipase, Urate and Cholesterol	Baseline (Pre-dose, Day-1) and up to Day 35	Blood samples were collected for analysis of clinical chemistry parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Glucose High, Grade 3: \>250 to 500 mg/dL, Grade 4: \>=500 mg/dL, Glucose Low, Grade 3: 30 to\<40 mg/dL, Grade 4:\<30 mg/dL; Triglycerides High, Grade 3: \>500 to \<1.000 mg/dL, Grade 4:\>1000 mg/dL; Lipase High, Grade 3: 3.0 to \<5.0×ULN, Grade 4:\>=5.0×ULN; Urate High, Grade 3: 12.0 to \<15.0 mEq/L, Grade 4:\>=15.0 mEq/L; Cholesterol High, Grade 3: \>=300 mg/dL, Grade 4: Not Applicable. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.
Cohort 2: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters: Alanine Aminotransferase, Albumin, Alkaline Phosphatase, Amylase, Aspartate Aminotransferase, Bilirubin and Direct Bilirubin	Baseline (Pre-dose, Day-1) and up to Day 36	Blood samples were collected for analysis of clinical chemistry parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Alanine Aminotransferase High; Grade 3: 5.0 to \<10.0 × ULN, Grade 4: \>=10.0 × ULN; Albumin Low, Grade 3: \<2.0 g/dL, Grade 4: Not Applicable; Alkaline Phosphatase High, Grade 3: 5.0 to \<10.0 × ULN, Grade 4: \>=10.0 × ULN; Amylase High, Grade 3: 3.0 to \<5.0 × ULN, Grade 4: \>=5.0 × ULN; Aspartate Aminotransferase High, Grade 3: 5.0 to \<10.0 × ULN, Grade 4: \>=10.0 × ULN; Bilirubin High, Grade 3: 2.6 to\<5.0 × ULN, Grade 4: \>=5.0 × ULN and Direct Bilirubin High, Grade 3: \>ULN with other signs and symptoms of hepatotoxicity, Grade 4: \>ULN with life-threatening consequences. Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.
Cohort 2: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters: Calcium, Creatine Kinase, Creatinine, Phosphate, Potassium and Sodium	Baseline (Pre-dose, Day-1) and up to Day 36	Blood samples were collected for analysis of clinical chemistry parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Calcium High, Grade 3: 12.5 to \<13.5 mg/dL, Grade 4: \>=13.5 mg/dL; Calcium Low, Grade 3: 6.1 to \<7.0 mg/dL, Grade 4: \<6.1 mg/dL; Creatine Kinase High, Grade 3: 10 to \<20 × ULN, Grade 4: \>=20 × ULN; Creatinine High, Grade 3: \>1.8 to \<3.5 ULN, Grade 4: \>=3.5 × ULN; Phosphate Low, Grade 3: 1.0 to \<1.4 mg/dL, Grade 4: \<1.0 mg/dL; Potassium High, Grade 3: 6.5 to \<7.0 mEq/L,Grade 4: \>=7.0 mEq/L; Potassium Low, Grade 3: 2.0 to \<2.5 mEq/L, Grade 4: \<2.00 mEq/L; Sodium High, Grade 3: 154 to \<160 mEq/L, Grade 4:\>=160 mEq/L; Sodium Low, Grade 3: 121 to \<125 mEq/L, Grade 4:\<=120 mEq/L. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.
Cohort 2: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters: Glucose, Triglycerides, Lipase, Urate and Cholesterol	Baseline (Pre-dose, Day-1) and up to Day 36	Blood samples were collected for analysis of clinical chemistry parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Glucose High, Grade 3: \>250 to 500 mg/dL, Grade 4: \>=500 mg/dL, Glucose Low, Grade 3: 30 to\<40 mg/dL, Grade 4:\<30 mg/dL; Triglycerides High, Grade 3: \>500 to \<1.000 mg/dL, Grade 4:\>1000 mg/dL; Lipase High, Grade 3: 3.0 to \<5.0×ULN, Grade 4:\>=5.0×ULN; Urate High, Grade 3: 12.0 to \<15.0 mEq/L, Grade 4:\>=15.0 mEq/L; Cholesterol High, Grade 3: \>=300 mg/dL, Grade 4: Not Applicable. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.
Cohort 3: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters: Alanine Aminotransferase, Albumin, Alkaline Phosphatase, Amylase, Aspartate Aminotransferase, Bilirubin and Direct Bilirubin	Baseline (Pre-dose, Day-1) and up to Day 26	Blood samples were collected for analysis of clinical chemistry parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Alanine Aminotransferase High; Grade 3: 5.0 to \<10.0 × ULN, Grade 4: \>=10.0 × ULN; Albumin Low, Grade 3: \<2.0 g/dL, Grade 4: Not Applicable; Alkaline Phosphatase High, Grade 3: 5.0 to \<10.0 × ULN, Grade 4: \>=10.0 × ULN; Amylase High, Grade 3: 3.0 to \<5.0 × ULN, Grade 4: \>=5.0 × ULN; Aspartate Aminotransferase High, Grade 3: 5.0 to \<10.0 × ULN, Grade 4: \>=10.0 × ULN; Bilirubin High, Grade 3: 2.6 to\<5.0 × ULN, Grade 4: \>=5.0 × ULN and Direct Bilirubin High, Grade 3: \>ULN with other signs and symptoms of hepatotoxicity, Grade 4: \>ULN with life-threatening consequences. Baseline was defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.
Cohort 3: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters: Calcium, Creatine Kinase, Creatinine, Phosphate, Potassium and Sodium	Baseline (Pre-dose, Day-1) and up to Day 26	Blood samples were collected for analysis of clinical chemistry parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Calcium High, Grade 3: 12.5 to \<13.5 mg/dL, Grade 4: \>=13.5 mg/dL; Calcium Low, Grade 3: 6.1 to \<7.0 mg/dL, Grade 4: \<6.1 mg/dL; Creatine Kinase High, Grade 3: 10 to \<20 × ULN, Grade 4: \>=20 × ULN; Creatinine High, Grade 3: \>1.8 to \<3.5 ULN, Grade 4: \>=3.5 × ULN; Phosphate Low, Grade 3: 1.0 to \<1.4 mg/dL, Grade 4: \<1.0 mg/dL; Potassium High, Grade 3: 6.5 to \<7.0 mEq/L,Grade 4: \>=7.0 mEq/L; Potassium Low, Grade 3: 2.0 to \<2.5 mEq/L, Grade 4: \<2.00 mEq/L; Sodium High, Grade 3: 154 to \<160 mEq/L, Grade 4:\>=160 mEq/L; Sodium Low, Grade 3: 121 to \<125 mEq/L, Grade 4:\<=120 mEq/L. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.
Cohort 3: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Clinical Chemistry Parameters: Glucose, Triglycerides, Lipase, Urate and Cholesterol	Baseline (Pre-dose, Day-1) and up to Day 26	Blood samples were collected for analysis of clinical chemistry parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Glucose High, Grade 3: \>250 to 500 mg/dL, Grade 4: \>=500 mg/dL, Glucose Low, Grade 3: 30 to\<40 mg/dL, Grade 4:\<30 mg/dL; Triglycerides High, Grade 3: \>500 to \<1.000 mg/dL, Grade 4:\>1000 mg/dL; Lipase High, Grade 3: 3.0 to \<5.0×ULN, Grade 4:\>=5.0×ULN; Urate High, Grade 3: 12.0 to \<15.0 mEq/L, Grade 4:\>=15.0 mEq/L; Cholesterol High, Grade 3: \>=300 mg/dL, Grade 4: Not Applicable. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.
Cohort 1: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Urinalysis Parameters	Baseline (Pre-dose, Day-1) and up to Day 35	Urine samples were collected for urinalysis parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Erythrocytes High, Grade 3: Gross, with or without clots OR with Red Blood Cells (RBC) casts OR intervention indicated, Grade 4: Life-threatening consequences; Glucose High, Grade 3: \>2+ (proportionate concentration by dipstick test) or \>500 mg, Grade 4: \>500 mg; Protein High, Grade 3: 3+ (proportionate concentration by dipstick test) or higher, Grade 4: Not Applicable. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.
Cohort 2: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Urinalysis Parameters	Baseline (Pre-dose, Day-1) and up to Day 36	Urine samples were collected for urinalysis parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Erythrocytes High, Grade 3: Gross, with or without clots OR with RBC casts OR intervention indicated, Grade 4: Life-threatening consequences; Glucose High, Grade 3: \>2+ (proportionate concentration by dipstick test) or \>500 mg, Grade 4: \>500 mg; Protein High, Grade 3: 3+ (proportionate concentration by dipstick test) or higher, Grade 4: Not Applicable. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.
Cohort 3: Number of Participants With Grade Increase Post-Baseline Relative to Baseline in Urinalysis Parameters	Baseline (Pre-dose, Day-1) and up to Day 26	Urine samples were collected for urinalysis parameters. Laboratory abnormalities were graded according to DAIDS grading table Version 2.1. For Erythrocytes High, Grade 3: Gross, with or without clots OR with RBC casts OR intervention indicated, Grade 4: Life-threatening consequences; Glucose High, Grade 3: \>2+ (proportionate concentration by dipstick test) or \>500 mg, Grade 4: \>500 mg; Protein High, Grade 3: 3+ (proportionate concentration by dipstick test) or higher, Grade 4: Not Applicable. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. An increase is defined as an increase in DAIDS grade relative to Baseline grade.
Cohort 3: Number of Participants With Vital Sign Values of PCI Criteria	Up to Day 26	Vital signs including SBP, DBP and pulse rate were measured in a supine position after atleast 5 minutes of rest. The PCI ranges for vitals were as follows; for SBP \<85 or \>140 mmHg, for DBP \<45 or \>90 mmHg, for pulse rate \<40 or \>100 beats per minute. The number of participants with vital signs of PCI were presented.
Cohort 1: Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) Findings	Day 1 (2,4,6 Hours), Day 7 and Day 11 in Treatment Period 1; Day 12 (2,4,6 Hours), Day 21 in Treatment Period 2; Day 22 (2,4,6 Hours), Day 26 and Day 35 in Treatment Period 3	A 12-lead ECG was recorded with the participant in a supine position using an automated ECG machine. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Data for number of participants with clinically significant abnormal ECG findings were reported. Data has been presented for the participants with respect to the actual treatment received in respective treatment periods.
Cohort 2: Number of Participants With Clinically Significant Abnormal ECG Findings	Day 1 (2,4,6 Hours), Day 7 and Day 11 in Treatment Period 1; Day 12 (2,4,6 Hours), Day 21 in Treatment Period 2; Day 22 (2,4,6 Hours), Day 26 and Day 36 in Treatment Period 3	A 12-lead ECG was recorded with the participant in a supine position using an automated ECG machine. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Data for number of participants with clinically significant abnormal ECG findings were reported. Data has been presented for the participants with respect to the actual treatment received in respective treatment periods.
Cohort 3: Number of Participants With Clinically Significant Abnormal ECG Findings	Day 1 (2,4,6 Hours) in Treatment Period 1; Day 8 (2,4,6 Hours), Day 9 (2,4,6 Hours), Day 26 in Treatment Period 2	A 12-lead ECG was recorded with the participant in a supine position using an automated ECG machine. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Data for number of participants with clinically significant abnormal ECG findings were reported. Data has been presented for the participants with respect to the actual treatment received in respective treatment periods.