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

Study Overview
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Brief Summary
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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.

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

Conditions
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Human Immunodeficiency Virus (HIV) Infection

Intervention / Treatment
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* Drug: Islatravir


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 |