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

Phase 1

Completed

Conditions: Human Immunodeficiency Virus (HIV) Infection

Interventions: Drug: Islatravir

Registration Number: NCT04515641

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Moderate Hepatic Impairment	Islatravir	Participants receive a single dose of ISL 60 mg.
Healthy Controls	Islatravir	Participants receive a single dose of ISL 60 mg.

Primary Outcome Measures

Name	Time	Method
Area Under the Curve From Time 0 to Infinity (AUC0-inf) of Islatravir (ISL) in Plasma	Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose	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.
Area Under the Curve From Time 0 to Last Sampling Time (AUC0-last) of ISL in Plasma	Pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose	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.
Maximum Concentration (Cmax) of ISL in Plasma	Pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose	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.
Time to Maximum Concentration (Tmax) of ISL in Plasma	Pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose	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.
Apparent Terminal Half-Life (t½) of ISL in Plasma	Pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose	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.
Apparent Volume of Distribution During Terminal Phase (Vz/F) of ISL in Plasma	Pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose	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.
Apparent Total Clearance (CL/F) of ISL in Plasma	Pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose	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.

Secondary Outcome Measures

Name	Time	Method
AUC0-inf of ISL Triphosphate (ISL-TP) in Peripheral Blood Mononuclear Cells (PBMC)	Predose and 4, 24, 48, 96, 168, 240, 336, 408, 504, and 672 hours post-dose	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.
Concentration at 672 Hours Post Dose (C672) of ISL-TP in PBMC	672 hours post-dose	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.
Percentage of Participants Who Discontinued From the Study Due to an AE	Up to 28 days	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.
AUC0-last of ISL-TP in PBMC	Predose and 4, 24, 48, 96, 168, 240, 336, 408, 504, and 672 hours post-dose	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.
Percentage of Participants With an Adverse Event (AE)	Up to 28 days	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.
Cmax of ISL-TP in PBMC	Predose and 4, 24, 48, 96, 168, 240, 336, 408, 504, and 672 hours post-dose	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.
Concentration at 24 Hours Post Dose (C24) of ISL-TP in PBMC	24 hours post-dose	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.
Tmax of ISL-TP in PBMC	Predose and 4, 24, 48, 96, 168, 240, 336, 408, 504, and 672 hours post-dose	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.
Concentration at 168 Hours Post Dose (C168) of ISL-TP in PBMC	168 hours post-dose	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.
T1/2 of ISL-TP in PBMC	Predose and 4, 24, 48, 96, 168, 240, 336, 408, 504, and 672 hours post-dose	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.