An Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of Islatravir (MK-8591) in Participants With Moderate Hepatic Impairment
Overview
- Phase
- Phase 1
- Intervention
- Islatravir
- Conditions
- Human Immunodeficiency Virus (HIV) Infection
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- Area Under the Curve From Time 0 to Infinity (AUC0-inf) of Islatravir (ISL) in Plasma
- Status
- Completed
- Last Updated
- 9 months ago
Overview
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.
Investigators
Eligibility Criteria
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:
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
Arms & Interventions
Moderate Hepatic Impairment
Participants receive a single dose of ISL 60 mg.
Intervention: Islatravir
Healthy Controls
Participants receive a single dose of ISL 60 mg.
Intervention: Islatravir
Outcomes
Primary Outcomes
Area Under the Curve From Time 0 to Infinity (AUC0-inf) of Islatravir (ISL) in Plasma
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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 Outcomes
- 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)
- Concentration at 672 Hours Post Dose (C672) of ISL-TP in PBMC(672 hours post-dose)
- Percentage of Participants Who Discontinued From the Study Due to an AE(Up to 28 days)
- AUC0-last of ISL-TP in PBMC(Predose and 4, 24, 48, 96, 168, 240, 336, 408, 504, and 672 hours post-dose)
- Percentage of Participants With an Adverse Event (AE)(Up to 28 days)
- Cmax of ISL-TP in PBMC(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(24 hours post-dose)
- Tmax of ISL-TP in PBMC(Predose and 4, 24, 48, 96, 168, 240, 336, 408, 504, and 672 hours post-dose)
- Concentration at 168 Hours Post Dose (C168) of ISL-TP in PBMC(168 hours post-dose)
- T1/2 of ISL-TP in PBMC(Predose and 4, 24, 48, 96, 168, 240, 336, 408, 504, and 672 hours post-dose)