Clinical trial NCT04515641: Single-Dose Islatravir in Moderate Hepatic Impairment (MK-8591-030)
Official title: An Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of Islatravir (MK-8591) in Participants With Moderate Hepatic Impairment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Human Immunodeficiency Virus (HIV) Infection
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2020-08-17
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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:

* 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

Primary outcomes:
measure: Area Under the Curve From Time 0 to Infinity (AUC0-inf) of Islatravir (ISL) in Plasma
timeFrame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose
measure: Area Under the Curve From Time 0 to Last Sampling Time (AUC0-last) of ISL in Plasma
timeFrame: Pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose
measure: Maximum Concentration (Cmax) of ISL in Plasma
timeFrame: Pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose
measure: Time to Maximum Concentration (Tmax) of ISL in Plasma
timeFrame: Pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose
measure: Apparent Terminal Half-Life (t½) of ISL in Plasma
timeFrame: Pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose
measure: Apparent Total Clearance (CL/F) of ISL in Plasma
timeFrame: Pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 168 hours post-dose
measure: Apparent Volume of Distribution During Terminal Phase (Vz/F) of ISL in Plasma
timeFrame: 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 outcomes:
measure: Percentage of Participants With an Adverse Event (AE)
timeFrame: Up to 28 days
measure: Percentage of Participants Who Discontinued From the Study Due to an AE
timeFrame: Up to 28 days
measure: AUC0-inf of ISL Triphosphate (ISL-TP) in Peripheral Blood Mononuclear Cells (PBMC)
timeFrame: Predose and 4, 24, 48, 96, 168, 240, 336, 408, 504, and 672 hours post-dose
measure: AUC0-last of ISL-TP in PBMC
timeFrame: Predose and 4, 24, 48, 96, 168, 240, 336, 408, 504, and 672 hours post-dose
measure: Cmax of ISL-TP in PBMC
timeFrame: Predose and 4, 24, 48, 96, 168, 240, 336, 408, 504, and 672 hours post-dose
measure: Concentration at 24 Hours Post Dose (C24) of ISL-TP in PBMC
timeFrame: 24 hours post-dose
measure: Concentration at 168 Hours Post Dose (C168) of ISL-TP in PBMC
timeFrame: 168 hours post-dose
measure: Concentration at 672 Hours Post Dose (C672) of ISL-TP in PBMC
timeFrame: 672 hours post-dose
measure: Tmax of ISL-TP in PBMC
timeFrame: Predose and 4, 24, 48, 96, 168, 240, 336, 408, 504, and 672 hours post-dose
measure: T1/2 of ISL-TP in PBMC
timeFrame: Predose and 4, 24, 48, 96, 168, 240, 336, 408, 504, and 672 hours post-dose
Other outcomes:
Locations:
city: Miami
country: United States
facility: Clinical Pharmacology of Miami ( Site 0001)
state: Florida
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: