Clinical trial NCT04303156: Pharmacokinetics of Islatravir in Participants With Severe Renal Impairment (MK-8591-026)
Official title: An Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of Islatravir (MK-8591) in Subjects With Severe Renal 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: 2020-03-10
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: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study will evaluate the general tolerability and pharmacokinetics (PK) of a single 60 mg dose of MK-8591 (Islatravir) in participants with severe renal insufficiency, compared to participants in good health.


Eligibility criteria: Inclusion Criteria:

Healthy participants must have the following:

* Is in good health
* Has a body mass index (BMI) ≥18.5 and ≤40 kg/m2.
* Female is not pregnant or breastfeeding, and is not one of the following: a woman of childbearing potential (WOCBP); if a WOCBP, is using an acceptable contraceptive method, or is abstinent from heterosexual intercourse as their preferred and usual lifestyle; a WOCBP must have a negative highly sensitive pregnancy test within 24 hours before the first dose of study intervention

Renally impaired participants must have the following:

* With the exception of renal impairment, is in generally good health
* Has a BMI ≥ 18.5 and ≤ 40 kg/m2
* Female is not pregnant or breastfeeding, and is not one of the following: a woman of childbearing potential (WOCBP); if a WOCBP, is using an acceptable contraceptive method, or is abstinent from heterosexual intercourse as their preferred and usual lifestyle; a WOCBP must have a negative highly sensitive pregnancy test within 24 hours before the first dose of study intervention

Exclusion Criteria:

Healthy participants must have the following:

* 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
* Has known hypersensitivity to the active substance or any of the excipients of the study drug
* Has a history of significant multiple and/or severe allergies (e.g. food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (i.e. systemic allergic reaction) to prescription or non-prescription drugs or food.
* Is positive for hepatitis B surface antigen, hepatitis C antibodies or HIV.
* Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within prior 4 weeks
* Is taking medications to treat chronic medical conditions and/or conditions associated with renal disease
* Has participated in another investigational study within prior 4 weeks

Other exclusions for healthy participants:

* Does not agree to follow the smoking restrictions
* Consumes greater than 1 glass for women, or 2 glasses for men of alcoholic beverages per day
* Consumes excessive amounts,of caffeinated beverages per day.
* Is a regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) abuse within approximately prior 3 months.

Renally impaired participants must have the following:

* Has a history or presence of renal artery stenosis.
* Has had a renal transplant or nephrectomy.
* Has rapidly fluctuating renal function as determined by historical measurements.
* Has known hypersensitivity to the active substance or any of the excipients of the study drug.
* Has a history of cancer (malignancy).
* Has a history of significant multiple and/or severe allergies (e.g. food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (i.e. systemic allergic reaction) to prescription or non-prescription drugs or food.
* Is positive for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus (HIV).
* Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the prestudy (screening) visit.
* Is taking medications to treat chronic medical conditions and/or conditions associated with renal disease and has not been on a stable regimen for at least 1 month and/or is unable to withhold the use of the medication(s) within 4 hours prior to and 8 hours after administration of the study drug.
* Has participated in another investigational study within 4 weeks (or 5 half-lives, whichever is greater) prior to the prestudy (screening) visit.

Other exclusions for renally impaired participants

* Does not agree to follow the smoking restrictions.
* Consumes greater than 1 glass for women, or 2 glasses for men of alcoholic beverages per day.
* Consumes excessive amounts of caffeinated beverages per day.
* Is a regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) abuse within approximately 3 months.

Primary outcomes:
measure: Area Under the Curve From Time 0 to Infinity (AUC0-inf) of Plasma Islatravir (ISL)
timeFrame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
measure: Area Under the Curve From Time 0 to Last Sampling Time (AUC0-last) of Plasma ISL
timeFrame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
measure: Maximum Concentration (Cmax) of Plasma ISL
timeFrame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
measure: Time of Maximum Concentration (Tmax) of Plasma ISL
timeFrame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
measure: Apparent Terminal Half-life (t1/2) of Plasma ISL
timeFrame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
measure: Apparent Clearance (CL/F) of Plasma ISL
timeFrame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
measure: Apparent Volume of Distribution (Vz/F) of Plasma ISL
timeFrame: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
Secondary outcomes:
measure: AUC0-inf of ISL Triphosphate (ISL-TP) in Peripheral Blood Mononuclear Cells (PBMC)
timeFrame: Pre-dose, 4, 24, 48, 96, 168 hours post-dose
measure: AUC0-last of ISL-TP in PBMC
timeFrame: Pre-dose, 4, 24, 48, 96, 168 hours post-dose
measure: Cmax of ISL-TP in PBMC
timeFrame: Pre-dose, 4, 24, 48, 96, 168 hours post-dose
measure: Tmax of ISL-TP in PBMC
timeFrame: Pre-dose, 4, 24, 48, 96, 168 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: T1/2 of ISL-TP in PBMC
timeFrame: Pre-dose, 4, 24, 48, 96, 168 hours post-dose
measure: Percentage of Participants With an Adverse Event (AE)
timeFrame: Up to Day 29
measure: Percentage of Participants Who Discontinued From the Study Due to an AE
timeFrame: Up to Day 29
Other outcomes:
Locations:
city: Miami
country: United States
facility: Clinical Pharmacology of Miami ( Site 0001)
state: Florida
city: Berlin
country: Germany
facility: Charite Research Organisation GmbH ( Site 0003)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Matthews RP, Cao Y, Patel M, Weissler VL, Bhattacharyya A, De Lepeleire I, Last S, Rondon JC, Vargo R, Stoch SA, Iwamoto M. Safety and Pharmacokinetics of Islatravir in Individuals with Severe Renal Insufficiency. Antimicrob Agents Chemother. 2022 Dec 20;66(12):e0093122. doi: 10.1128/aac.00931-22. Epub 2022 Nov 8.