Study to Evaluate the Pharmacokinetic (PK) Interactions Between GSK3640254 and Dolutegravir (DTG)

NCT03816696 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 209712
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-label, single-sequence, two-way drug interaction study to investigate the PK, safety and tolerability of GSK3640254 and DTG when administered alone or in combination in healthy subjects. Treatment of human immunodeficiency virus (HIV) infection frequently involves combination therapy. Data from this study will contribute to dosing recommendations when GSK3640254 and DTG are given in combination. The study will consist of a Screening period and 3 sequential treatment periods. Subjects will be administered DTG 50 milligrams (mg) once daily (QD) in Period 1 followed by GSK3640254 200 mg QD in Period 2. There will be a washout period of 4 days between Periods 1 and 2. In Period 3, subjects will be co-administered DTG 50 mg QD and GSK3640254 200 mg QD. The total duration of the study will be approximately 55 days, including Screening.

Conditions

HIV Infections

Keywords

GSK3640254, dolutegravir, healthy subjects, two-way interaction, HIV

Outcome Measures

Primary Outcomes (12)

• Period 1: Area Under the Plasma Concentration-time Curve From Time 0 to the End of the Dosing (AUC[0 to Tau]) of Dolutegravir for Dolutegravir Arm

  Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. Pharmacokinetic Parameter Population consisted of all participants who underwent plasma pharmacokinetic sampling and had evaluable pharmacokinetic parameters estimated.

  Day 5: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose

• Period 3: AUC(0 to Tau) of Dolutegravir for Dolutegravir + GSK3640254 Arm

  Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  Day 7: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose

• Period 1: Maximum Observed Concentration (Cmax) of Dolutegravir for Dolutegravir Arm

  Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  Day 5: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose

• Period 3: Cmax of Dolutegravir for Dolutegravir + GSK3640254 Arm

  Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  Day 7: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose

• Period 1: Plasma Concentration at the End of the Dosing Interval (Ctau) of Dolutegravir for Dolutegravir Arm

  Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  Day 5: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose

• Period 3: Ctau of Dolutegravir for Dolutegravir + GSK3640254 Arm

  Blood samples were collected at the indicated time points for pharmacokinetic analysis of dolutegravir. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  Day 7: Pre-dose, 1, 1.5, 2, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose

• Period 2: AUC(0 to Tau) of GSK3640254 for GSK3640254 Arm

  Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose

• Period 3: AUC(0 to Tau) of GSK3640254 for Dolutegravir + GSK3640254 Arm

  Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose

• Period 2: Cmax of GSK3640254 for GSK3640254 Arm

  Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose

• Period 3: Cmax of GSK3640254 for Dolutegravir + GSK3640254 Arm

  Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose

• Period 2: Ctau of GSK3640254 for GSK3640254 Arm

  Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose

• Period 3: Ctau of GSK3640254 for Dolutegravir + GSK3640254 Arm

  Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK3640254. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  Day 7: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12 and 24 hours post-dose

Secondary Outcomes (126)

• Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs)

  Up to Day 27

• Period 1: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet Count

  Baseline (Day -1) and at Day 9

• Period 2: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet Count

  Baseline (Period 1 Day 9) and at Day 7

• Period 3: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet Count

  Baseline (Period 2 Day 7) and at Days 4, 7 and 10

• Period 1: Change From Baseline in Hematology Parameter: Hemoglobin

  Baseline (Day -1) and at Day 9

Study Arms (1)

DTG followed by GSK3640254 followed by DTG+GSK3640254

EXPERIMENTAL

Subjects will receive DTG 50 mg QD on Days 1 through 5 in Period 1 followed by a wash-out period of 4 days. Subjects will then receive GSK3640254 200 mg QD on Days 1 through 7 in Period 2 followed by co-administration of DTG 50 mg QD with GSK3640254 200 mg QD on Days 1 through 7 in Period 3.

Drug: GSK3640254; Drug: DTG

Interventions

GSK3640254 DRUG

GSK3640254 will be available as 100 mg capsules. Subjects will be administered GSK3640254 200 mg QD via the oral route.

DTG followed by GSK3640254 followed by DTG+GSK3640254

DTG DRUG

DTG will be available as 50 mg tablets. Subjects will be administered DTG 50 mg QD via the oral route.

DTG followed by GSK3640254 followed by DTG+GSK3640254

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subject must be 18 to 55 years of age inclusive, at the time of signing the informed consent.
• Subjects who are healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring (history and ECG).
• Body weight \>=50 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 subjects can participate. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and not a woman of childbearing potential (WOCBP).
• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol.

You may not qualify if:

• 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 (e.g., gastroesophageal reflux disease, gastric ulcers, gastritis), hepatic and/or renal function, that could interfere with the absorption, metabolism, and/or excretion of the study drugs or render the subject unable to take oral study intervention.
• 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 (\>6 months) outpatient treatment. Subjects 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 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 subject's ability to comply with the dosing schedule and protocol evaluations or which might compromise the safety of the subject.
• Medical history of cardiac arrhythmias or cardiac disease or a family or personal history of long QT syndrome.
• Presence of Hepatitis B surface antigen (HBsAg) 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 and positive on reflex to Hepatitis C ribonucleic acid (RNA).
• Positive HIV-1 and -2 antigen/antibody immunoassay at Screening.
• 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 percent).
• Any acute laboratory abnormality at Screening which, in the opinion of the investigator, should preclude participation in the study of an investigational compound.
• Any Grade 2 to 4 laboratory abnormality at Screening, with the exception of creatine phosphokinase (CPK) and lipid abnormalities (e.g., total cholesterol, triglycerides), and ALT (described above), will exclude a subject from the study unless the investigator can provide a compelling explanation for the laboratory results and has the assent of the sponsor. A single repeat of any laboratory abnormality is allowed within a single screening period to determine eligibility.
• A positive test result for drugs of abuse (including marijuana), alcohol, or cotinine (indicating active current smoking) at Screening or before the first dose of study intervention.
• Unable to refrain from the use of prescription or non-prescription drugs including vitamins, herbal and dietary supplements (including St John's wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication and for the duration of the study.

Sponsors & Collaborators

• ViiV Healthcare: lead

Study Sites (1)

GSK Investigational Site

Austin, Texas, 78744, United States

Location

Related Publications (1)

• Pene Dumitrescu T, Joshi SR, Xu J, Greene TJ, Johnson M, Butcher L, Zimmerman E, Webster L, Pham TT, Lataillade M, Min S. Phase I evaluation of pharmacokinetics and tolerability of the HIV-1 maturation inhibitor GSK3640254 and dolutegravir in healthy adults. Br J Clin Pharmacol. 2021 Sep;87(9):3501-3507. doi: 10.1111/bcp.14759. Epub 2021 Mar 4.

  PMID: 33533507 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

GSK3640254

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

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: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 22, 2019
• First Posted: January 25, 2019
• Study Start: January 23, 2019
• Primary Completion: March 30, 2019
• Study Completion: April 10, 2019
• Last Updated: March 19, 2020
• Results First Posted: March 19, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the 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 can be granted, when justified, for up to another 12 months.

Locations

US (1)