Study to Evaluate the Effect of GSK3640254 on the Pharmacokinetics of Tenofovir Alafenamide/Emtricitabine

NCT03836729 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 208134
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

Human immunodeficiency virus (HIV) infection frequently involves combination drug therapy for its treatment; hence, it is important to understand their interactions and resulting changes in exposure which are associated with medications. This is a Phase-1, open-label, fixed-sequence 2-period, one-way drug interaction study to assess the pharmacokinetic (PK), safety, and tolerability of GSK3640254 and Tenofovir alafenamide/emtricitabine (TAF/FTC) when administered alone and in combination in healthy subjects. The study will consist of a screening period of 28 days before the first dose of study intervention followed by 2 sequential treatment periods. Subjects will be administered TAF/FTC 25/200 milligram (mg) once daily (QD) on Days 1 to 14 of Period 1 followed by co-administration of TAF/FTC 25/200 mg QD with GSK3640254 200 mg QD on Days 1 to 7 of Period 2.

Conditions

HIV Infections

Keywords

Human immunodeficiency virus; Sequential; Tenofovir alafenamide; Emtricitabine; GSK3640254

Outcome Measures

Primary Outcomes (16)

• Period 1: Area Under the Plasma Concentration-time Curve From Time 0 to the End of the Dosing Interval at Steady State (AUC [0-tau]) of TAF

  Blood samples were collected at indicated time-points for analysis of AUC (0-tau). Pharmacokinetic (PK) parameters were calculated by standard non-compartmental analysis. PK Parameter Population included all participants who underwent plasma PK sampling and had evaluable PK parameters estimated.

  Pre-dose, 15, 30, 45 minutes, 1 hour, 1 hour 30 minutes, 2, 3, 4, 5, 6, 8, 12 and 24 hours in Period 1 Day 14

• Period 2: AUC (0-tau) of TAF

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

  Pre-dose, 15, 30, 45 minutes, 1 hour, 1 hour 30 minutes, 2, 3, 4, 5, 6, 8, 12 and 24 hours in Period 2 Day 7

• Period 1: Maximum Observed Concentration (Cmax) of TAF

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

  Pre-dose, 15, 30, 45 minutes, 1 hour, 1 hour 30 minutes, 2, 3, 4, 5, 6, 8, 12 and 24 hours in Period 1 Day 14

• Period 2: Cmax of TAF

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

  Pre-dose, 15, 30, 45 minutes, 1 hour, 1 hour 30 minutes, 2, 3, 4, 5, 6, 8, 12 and 24 hours in Period 2 Day 7

• Period 1: AUC (0-tau) of FTC

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

  Pre-dose, 15, 30, 45 minutes, 1 hour, 1 hour 30 minutes, 2, 3, 4, 5, 6, 8, 12 and 24 hours in Period 1 Day 14

• Period 2: AUC (0-tau) of FTC

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

  Pre-dose, 15, 30, 45 minutes, 1 hour, 1 hour 30 minutes, 2, 3, 4, 5, 6, 8, 12 and 24 hours in Period 2 Day 7

• Period 1:Cmax of FTC

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

  Pre-dose, 15, 30, 45 minutes, 1 hour, 1 hour 30 minutes, 2, 3, 4, 5, 6, 8, 12 and 24 hours in Period 1 Day 14

• Period 2:Cmax of FTC

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

  Pre-dose, 15, 30, 45 minutes, 1 hour, 1 hour 30 minutes, 2, 3, 4, 5, 6, 8, 12 and 24 hours in Period 2 Day 7

• Period 1: Plasma Concentration at the End of the Dosing Interval (Ctau) of FTC

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

  Pre-dose, 15, 30, 45 minutes, 1 hour, 1 hour 30 minutes, 2, 3, 4, 5, 6, 8, 12 and 24 hours in Period 1 Day 14

• Period 2: Ctau of FTC

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

  Pre-dose, 15, 30, 45 minutes, 1 hour, 1 hour 30 minutes, 2, 3, 4, 5, 6, 8, 12 and 24 hours in Period 2 Day 7

• Period 1: AUC (0-tau) of Tenofovir (TFV)

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

  Pre-dose, 15, 30, 45 minutes, 1 hour, 1 hour 30 minutes, 2, 3, 4, 5, 6, 8, 12 and 24 hours in Period 1 Day 14

• Period 2: AUC (0-tau) of TFV

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

  Pre-dose, 15, 30, 45 minutes, 1 hour, 1 hour 30 minutes, 2, 3, 4, 5, 6, 8, 12 and 24 hours in Period 2 Day 7

• Period 1: Cmax of TFV

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

  Pre-dose, 15, 30, 45 minutes, 1 hour, 1 hour 30 minutes, 2, 3, 4, 5, 6, 8, 12 and 24 hours in Period 1 Day 14

• Period 2: Cmax of TFV

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

  Pre-dose, 15, 30, 45 minutes, 1 hour, 1 hour 30 minutes, 2, 3, 4, 5, 6, 8, 12 and 24 hours in Period 2 Day 7

• Period 1: Ctau of TFV

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

  Pre-dose, 15, 30, 45 minutes, 1 hour, 1 hour 30 minutes, 2, 3, 4, 5, 6, 8, 12 and 24 hours in Period 1 Day 14

• Period 2: Ctau of TFV

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

  Pre-dose, 15, 30, 45 minutes, 1 hour, 1 hour 30 minutes, 2, 3, 4, 5, 6, 8, 12 and 24 hours in Period 2 Day 7

Secondary Outcomes (91)

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

  Up to Day 24

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

  Baseline and at Days 7, and 14

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

  Baseline and at Days 3, 7, 9

• Period 1: Absolute Values of the Hematology Parameter of Platelet Count, Neutrophils, Lymphocytes, Monocytes, Eosinophils and Basophils

  Baseline and at Days 7, and 14

• Period 2: Absolute Values of the Hematology Parameter of Platelet Count, Neutrophils, Lymphocytes, Monocytes, Eosinophils and Basophils

  Baseline and at Days 3, 7, 9

Study Arms (1)

TAF/FTC followed by TAF/FTC + GSK3640254

EXPERIMENTAL

Subjects will receive TAF/FTC 25/200 mg QD on Days 1 through 14 in Treatment Period 1. Subjects will be co-administered TAF/FTC 25/200 mg QD with GSK3640254 200 mg QD on Days 1 through 7 in Treatment Period 2.

Drug: Tenofovir alafenamide/emtricitabine; Drug: GSK3640254

Interventions

Tenofovir alafenamide/emtricitabine DRUG

TAF/FTC will be available as 25/200 milligrams (mg) tablet. Subjects will be administered TAF/FTC 25/200 mg QD via the oral route.

TAF/FTC followed by TAF/FTC + GSK3640254

GSK3640254 DRUG

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

TAF/FTC followed by TAF/FTC + 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 \>=50.0 kilograms (kg) (110 pound \[lbs\]) for men and \>=45.0 kilograms \[kg\] (99 lbs) for women and body mass index (BMI) within the range 18.5 to 31.0 kilograms per meter square (kg/m\^2) (inclusive).
• Male or female; 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.
• History of any kidney disease or current or chronic history of impaired renal function as indicated by an estimated creatinine clearance \<80 milliliters per minute (mL/min). Creatinine clearance (CrCL) is estimated by either of the following methods: (a) The Modification of Diet in Renal Disease (MDRD) equation: estimated glomerular filtration rate (eGFR) (milliliter \[mL\]/minute \[min\]/1.73 meter square \[m\^2\]) = 175 x (SCr)\^-1.154 x (Age)\^-0.203 x 0.742 \[if female\] x 1.212 \[if African American\] glomerular filtration rate (GFR) is expressed in mL/min/1.73 m\^2, SCr is serum creatinine expressed in milligrams per deciliter (mg/dL), and age is expressed in years. (b)The Cockcroft-Gault equation: CrCL(mL/min) ={((l40-age) x weight)/(72xSCr)}x 0.85 (if female) CrCL is expressed in mL/min, age is expressed in years, weight is expressed in kg, and SCr is serum creatinine expressed in mg/dL.
• 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 × upper limit of normal (ULN). A single repeat of ALT is allowed within a single screening period to determine eligibility.
• Bilirubin \>1.5 × ULN (isolated bilirubin \>1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
• 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, etc), and ALT (described above), will exclude a subject from the study unless the investigator can provide a compelling explanation for the laboratory result(s) 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.

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, Zhan J, Johnson M, Butcher L, Zimmerman E, Webster L, Davidson AM, Lataillade M, Min S. A Phase I Evaluation of the Pharmacokinetics and Tolerability of the HIV-1 Maturation Inhibitor GSK3640254 and Tenofovir Alafenamide/Emtricitabine in Healthy Participants. Antimicrob Agents Chemother. 2021 May 18;65(6):e02173-20. doi: 10.1128/AAC.02173-20. Print 2021 May 18.

  PMID: 33753329 DERIVED

MeSH Terms

Conditions

HIV Infections; Acquired Immunodeficiency Syndrome

Interventions

emtricitabine tenofovir alafenamide; 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; Slow Virus Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: ViiV Healthcare

GSKClinicalSupportHD@gsk.com

8664357343

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
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a fixed-sequence 2-period, one-way drug interaction study

Study Record Dates

• First Submitted: February 7, 2019
• First Posted: February 11, 2019
• Study Start: February 11, 2019
• Primary Completion: March 30, 2019
• Study Completion: April 30, 2019
• Last Updated: April 21, 2020
• Results First Posted: April 2, 2020

Record last verified: 2020-04

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)