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

NCT04630002 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 213054
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 1

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.

Conditions

HIV Infections

Keywords

Darunavir; Ritonavir; Etravirine; GSK3640254; Pharmacokinetics

Outcome Measures

Primary Outcomes (12)

• 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

  Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

  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

• Cohort 1: Maximum Observed Concentration (Cmax) of GSK3640254

  Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

  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

• Cohort 1: AUC(0-tau) of DRV

  Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

  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

• Cohort 1: Cmax of DRV

  Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

  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

• Cohort 1: AUC(0-tau) of RTV

  Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

  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

• Cohort 1: Cmax of RTV

  Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

  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

• Cohort 2: AUC(0-tau) of GSK3640254

  Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

  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

• Cohort 2: Cmax of GSK3640254

  Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

  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

• Cohort 2: AUC(0-tau) of ETR

  Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

  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

• Cohort 2: Cmax of ETR

  Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

  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

• Cohort 3: AUC(0-tau) of GSK3640254

  Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

  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

• Cohort 3: Cmax of GSK3640254

  Blood samples were collected at indicated time points. Pharmacokinetic analysis was conducted using standard non-compartmental methods.

  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

Secondary Outcomes (37)

• 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

• 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

• 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

• 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

• 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

Study Arms (3)

Cohort 1: GSK3640254 then DRV/RTV then GSK3640254 + DRV/RTV

EXPERIMENTAL

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.

Drug: GSK3640254; Drug: Darunavir/Ritonavir (DRV/RTV)

Cohort 2: GSK3640254 then ETR then GSK3640254 + ETR

EXPERIMENTAL

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.

Drug: GSK3640254; Drug: Etravirine (ETR)

Cohort 3: GSK3640254 then GSK3640254 + DRV/RTV + ETR

EXPERIMENTAL

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.

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

Interventions

GSK3640254 DRUG

GSK3640254 will be available as oral tablets.

Cohort 1: GSK3640254 then DRV/RTV then GSK3640254 + DRV/RTV; Cohort 2: GSK3640254 then ETR then GSK3640254 + ETR; Cohort 3: GSK3640254 then GSK3640254 + DRV/RTV + ETR

Darunavir/Ritonavir (DRV/RTV) DRUG

DRV/RTV will be available as oral tablets.

Cohort 1: GSK3640254 then DRV/RTV then GSK3640254 + DRV/RTV; Cohort 3: GSK3640254 then GSK3640254 + DRV/RTV + ETR

Etravirine (ETR) DRUG

ETR will be available as oral tablets.

Cohort 2: GSK3640254 then ETR then GSK3640254 + ETR; Cohort 3: GSK3640254 then GSK3640254 + DRV/RTV + ETR

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Participant must be 18 to 50 years of age inclusive, at the time of signing the informed consent.
• Participants who are overtly healthy as determined by investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring (history and screening ECG).
• Body weight more than or equal to (\>=)50.0 kilograms (kg) (110 pounds \[lbs\]) for men and \>=45.0 kg (99 lbs) for women and body mass index within the range 18.5 to 31.0 kilograms per square meter (kg/m\^2) (inclusive).
• Male or female participants:
• Male participants should not engage in intercourse while confined in the study site. There is no need for an extended period of double barrier use or prolonged abstinence after study discharge.
• Female participants:
• (i) A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: Is not a woman of childbearing potential (WOCBP) OR Is a WOCBP and using a non-hormonal contraceptive method that is highly effective, with a failure rate of less than (\<)1 percent (%) for 28 days before intervention, during the intervention period, and for at least 28 days after the last dose of study intervention. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
• (ii) A WOCBP must have a negative highly sensitive serum or urine pregnancy test at screening and check-in (Day -1).
• 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.

You may not qualify if:

• Participants with current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• A pre-existing condition interfering with normal Gastrointestinal (GI) anatomy or motility (for example \[e.g.\], gastroesophageal reflux disease, gastric ulcers, gastritis) or hepatic and/or renal function that could interfere with the absorption, metabolism, and/or excretion of the study intervention or render the participant unable to take oral study intervention.
• Prior cholecystectomy surgery (prior appendectomy is acceptable).
• Clinically significant illness, including viral syndromes within 3 weeks of dosing.
• A participant with known or suspected active Coronavirus Disease-2019 (COVID-19) infection or contact with an individual with known COVID-19, within 14 days of study enrollment (World Health Organization \[WHO\] definitions).
• Any history of significant underlying psychiatric disorder, including, but not limited to, schizophrenia, bipolar disorder with or without psychotic symptoms, other psychotic disorders, or schizotypal (personality) disorder.
• Any history of major depressive disorder with or without suicidal features, or anxiety disorders that required medical intervention (pharmacologic or not) such as hospitalization or other inpatient treatment and/or chronic (more than \[\>\]6 months) outpatient treatment. Participants with other conditions such as adjustment disorder or dysthymia that have required shorter term medical therapy (\<6 months) without inpatient treatment and are currently well-controlled clinically or resolved may be considered for entry after discussion and agreement with the ViiV Healthcare/GlaxoSmithKline (VH/GSK) medical monitor.
• Any pre-existing physical or other psychiatric condition (including alcohol or drug abuse), which, in the opinion of the investigator (with or without psychiatric evaluation), could interfere with the participant's ability to comply with the dosing schedule and protocol evaluations or which might compromise the safety of the participant.
• Medical history of cardiac arrhythmias, prior myocardial infarction in the past 3 months, or cardiac disease or a family or personal history of long QT syndrome.
• Presence of hepatitis B surface antigen at screening or within 3 months prior to starting study intervention.
• Positive hepatitis C antibody test result at screening or within 3 months prior to starting study intervention.
• Positive Human immunodeficiency virus (HIV)-1 and -2 antigen/antibody immunoassay at screening.
• Alanine aminotransferase (ALT) \>1.5 times upper limit of normal (ULN). A single repeat of ALT is allowed within a single screening period to determine eligibility.
• Bilirubin \>1.5 times ULN (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). A single repeat of any laboratory abnormality is allowed within a single screening period to determine eligibility.
• Any acute laboratory abnormality at screening which, in the opinion of the investigator, should preclude participation in the study of an investigational compound.

Sponsors & Collaborators

• ViiV Healthcare: lead

Study Sites (1)

GSK Investigational Site

Austin, Texas, 78744, United States

Location

Related Publications (1)

• Zhang Y, Joshi S, Yazdani P, Zhan J, Wen B, Bainbridge V, Ballesteros-Perez A, Gartland M, Lataillade M. Pharmacokinetics and tolerability of the maturation inhibitor GSK3640254 coadministered with darunavir/ritonavir and/or etravirine in healthy adults. Br J Clin Pharmacol. 2024 Jan;90(1):274-285. doi: 10.1111/bcp.15893. Epub 2023 Sep 20.

  PMID: 37621050 BACKGROUND

MeSH Terms

Conditions

HIV Infections

Interventions

GSK3640254; Darunavir; Ritonavir; etravirine

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Carbamates; Acids, Acyclic; Carboxylic Acids; Sulfones; Sulfur Compounds; Furans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Thiazoles; Azoles

Results Point of Contact

• Title: GSK Response Center
• Organization: ViiV Healthcare

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: This is an open-label study.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is an open-label, single-sequence, multiple-dose and 3-cohort study.

Study Record Dates

• First Submitted: November 11, 2020
• First Posted: November 16, 2020
• Study Start: October 28, 2020
• Primary Completion: October 2, 2021
• Study Completion: October 2, 2021
• Last Updated: August 29, 2024
• Results First Posted: August 21, 2023

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Anonymized IPD is made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or terminated asset(s) across all indications.
• Access Criteria: Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension may be granted, when justified, for up to 6 months.

Locations

US (1)