Single-Dose Islatravir in Moderate Hepatic Impairment (MK-8591-030)

An Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of Islatravir (MK-8591) in Participants With Moderate Hepatic Impairment

This is an open-label, single-dose study of the plasma pharmacokinetics (PK), safety, and tolerability of islatravir (ISL, MK-8591), and the intracellular PK of ISL triphosphate (ISL-TP) in male and female adult participants with moderate hepatic impairment and in healthy matched control participants.

Study Overview

• Status: Completed
• Conditions: Human Immunodeficiency Virus (HIV) Infection
• Intervention / Treatment: Drug: Islatravir

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33014
      • Clinical Pharmacology of Miami ( Site 0001)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Healthy Control Participants:

• Is in good health based on medical history, physical examination, vital sign (VS) measurements and electrocardiograms (ECGs) performed prior to randomization
• Is in good health based on laboratory safety tests obtained at the screening visit and prior to administration of the initial dose of study drug.
• Has a body mass index (BMI) ≥18.5 and ≤40 kg/m2

Hepatic Impairment Participants:

• Has a diagnosis of chronic (> 6 months), stable (no acute episodes of illness within the previous 2 months due to deterioration in hepatic function) hepatic insufficiency with features of cirrhosis due to any etiology
• Has a score on the Child-Pugh scale ranging from 7 to 9 (moderate hepatic insufficiency) at screening
• With the exception of hepatic impairment, is in generally good health
• Has a BMI ≥ 18.5 and ≤ 40 kg/m2

Healthy and Hepatic Impairment Participants:

• Males : uses contraception according to local regulations
• Females: is not pregnant or breastfeeding and one of the following applies:
• Is not a woman of childbearing potential (WOCBP) OR
• Is a WOCBP and uses an acceptable contraceptive method
• A WOCBP with negative highly sensitive pregnancy test within 24 hours of study intervention

Exclusion Criteria:

• Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases
• Is mentally or legally incapacitated, has significant emotional problems at the time of prestudy (screening) visit or expected during the conduct of the study or has a history of clinically significant psychiatric disorder of the last 5 years
• Has a history of cancer (malignancy)
• Has a history of significant multiple and/or severe allergies, or has had an anaphylactic reaction or significant intolerability (ie, systemic allergic reaction) to prescription or non-prescription drugs or food
• Has known hypersensitivity to the active substance or any of the excipients of the study drug
• Is positive for hepatitis B surface antigen, hepatitis C antibodies, HIV-1 or HIV-2
• Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the prestudy (screening) visit
• Is unable to refrain from or anticipates the use of any medication, including prescription and nonprescription drugs or herbal remedies beginning approximately 2 weeks (or 5 half-lives) prior to study drug administration, throughout the study, until the poststudy visit
• Has participated in another investigational study within 4 weeks (or 5 half-lives, whichever is greater) prior to the prestudy (screening) visit
• Has a QTc interval >470 for males or >480 ms for females, has a history of risk factors for Torsades de Pointes (eg, heart failure/cardiomyopathy or family history of long QT syndrome), has uncorrected hypokalemia or hypomagnesemia, is taking concomitant medications that prolong the QT/QTc interval
• Is not considered low risk of having HIV infection
• Is a smoker or user of electronic cigarettes and/or has used nicotine or nicotine-containing products (eg, nicotine patch) within 3 months of screening
• Consumes greater than 3 glasses of alcoholic beverages per day
• Consumes more than 6 caffeinated beverages per day
• Is a regular user of illicit drugs or has a history of drug abuse within 2 years
• Presents any concern to the investigator regarding safe study participation
• Is unwilling to comply with study restrictions
• Is or has an immediate family member who is investigational site or Sponsor staff directly involved with this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Moderate Hepatic Impairment; Participants receive a single dose of ISL 60 mg.	Drug: Islatravir; Two ISL 30 mg capsules taken by mouth.; Other Names: MK-8591
Experimental: Healthy Controls; Participants receive a single dose of ISL 60 mg.	Drug: Islatravir; Two ISL 30 mg capsules taken by mouth.; Other Names: MK-8591

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve From Time 0 to Infinity (AUC0-inf) of Islatravir (ISL) in Plasma	Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose
Area Under the Curve From Time 0 to Last Sampling Time (AUC0-last) of ISL in Plasma	Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	Pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose
Maximum Concentration (Cmax) of ISL in Plasma	Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	Pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose
Time to Maximum Concentration (Tmax) of ISL in Plasma	Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The Tmax of plasma ISL was expressed as a median.	Pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose
Apparent Terminal Half-Life (t½) of ISL in Plasma	Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The Geometric Coefficient of Variation was expressed as a percent (%CV), and is calculated from the square root of corresponding estimated variance obtained for each population in fixed effect model multiplied by 100.	Pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose
Apparent Total Clearance (CL/F) of ISL in Plasma	Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The Geometric Coefficient of Variation was expressed as a percent (%CV), and is calculated from the square root of corresponding estimated variance obtained for each population in fixed effect model multiplied by 100.	Pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose
Apparent Volume of Distribution During Terminal Phase (Vz/F) of ISL in Plasma	Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The Geometric Coefficient of Variation was expressed as a percent (%CV), and is calculated from the square root of corresponding estimated variance obtained for each population in fixed effect model multiplied by 100.	Pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration at 24 Hours Post Dose (C24) of ISL-TP in PBMC	Participants were treated with ISL and peripheral blood samples were collected at 24 hours post-dose to determine the concentration of ISL-TP in PBMCs. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	24 hours post-dose
Concentration at 168 Hours Post Dose (C168) of ISL-TP in PBMC	Participants were treated with ISL and peripheral blood samples were collected at 168 hours post-dose to determine the concentration of ISL-TP in PBMCs. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	168 hours post-dose
Concentration at 672 Hours Post Dose (C672) of ISL-TP in PBMC	Participants were treated with ISL and peripheral blood samples were collected at 672 hours post-dose to determine the concentration of ISL-TP in PBMCs. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	672 hours post-dose
Percentage of Participants With an Adverse Event (AE)	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.	Up to 28 days
Percentage of Participants Who Discontinued From the Study Due to an AE	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.	Up to 28 days
AUC0-inf of ISL Triphosphate (ISL-TP) in Peripheral Blood Mononuclear Cells (PBMC)	Participants were treated with ISL, and peripheral blood samples were collected from pre-dose up to 672 hours post-dose to determine the concentration of ISL-TP in PBMCs. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	Predose and 4, 24, 48, 96, 168, 240, 336, 408, 504, and 672 hours post-dose
AUC0-last of ISL-TP in PBMC	Participants were treated with ISL and peripheral blood samples were collected from pre-dose up to 672 hours post-dose to determine the concentration of ISL-TP in PBMCs. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	Predose and 4, 24, 48, 96, 168, 240, 336, 408, 504, and 672 hours post-dose
Cmax of ISL-TP in PBMC	Participants were treated with ISL and peripheral blood samples were collected from pre-dose up to 672 hours post-dose to determine the concentration of ISL-TP in PBMCs. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	Predose and 4, 24, 48, 96, 168, 240, 336, 408, 504, and 672 hours post-dose
Tmax of ISL-TP in PBMC	Participants were treated with ISL and peripheral blood samples were collected from pre-dose up to 672 hours post-dose to determine the concentration of ISL-TP in PBMCs. The Tmax of ISL-TP was expressed as a median.	Predose and 4, 24, 48, 96, 168, 240, 336, 408, 504, and 672 hours post-dose
T1/2 of ISL-TP in PBMC	Participants were treated with ISL, and peripheral blood samples were collected from pre-dose to 672 hours post-dose to determine the concentration of ISL-TP in PBMCs. The Geometric Coefficient of Variation was expressed as a percent (%CV), and is calculated from the square root of corresponding estimated variance obtained for each population in fixed effect model multiplied by 100.	Predose and 4, 24, 48, 96, 168, 240, 336, 408, 504, and 672 hours post-dose

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): November 5, 2020
• Primary Completion (Actual): September 13, 2021
• Study Completion (Actual): September 13, 2021

Study Registration Dates

• First Submitted: August 14, 2020
• First Submitted That Met QC Criteria: August 14, 2020
• First Posted (Actual): August 17, 2020

Study Record Updates

• Last Update Posted (Actual): July 3, 2023
• Last Update Submitted That Met QC Criteria: July 25, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; Urogenital Diseases; Genital Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Retroviral Agents; Islatravir
• Other Study ID Numbers: 8591-030; MK-8591-030 (Other Identifier: Merck)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No