Clinical trial NCT02666352: A Study of the Pharmacokinetics of Uprifosbuvir (MK-3682) and Ruzasvir (MK-8408) in Participants With Moderate and Severe Hepatic Insufficiency (MK-3682-029)
Official title: A Two-Part, Open-Label Study to Investigate the Single-Dose Pharmacokinetics of MK-3682 and MK-8408 When Coadministered to Subjects With Moderate and Severe Hepatic Insufficiency
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatitis C, Chronic
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2016-01-28
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a non-randomized, open-label, single-dose study to evaluate the pharmacokinetics (PK) of uprifosbuvir (MK-3682), the M5 and M6 metabolites of uprifosbuvir, and ruzasvir (MK-8408), in participants with moderate hepatic insufficiency (HI), participants with severe HI, and age-matched healthy control participants.


Eligibility criteria: Inclusion Criteria:

HI Participants Only:

* Has a diagnosis of chronic (\>6 months), stable (no acute episodes of illness within the previous 2 months due to deterioration in hepatic function) HI features of cirrhosis;
* Part 1 only: Participant's score on the Child-Pugh scale ranges from 7 to 9 (moderate HI) at study start.
* Part 2 only: Participant's score on the Child-Pugh scale ranges from 10 to 15 (severe HI) at study start.

All Participants:

* Body mass index (BMI) ≥19 and ≤ 40 kg/m\^2;
* Continuous non-smokers or moderate smokers (of fewer than 20 cigarettes/day or the equivalent). Participants must agree to consume no more than 10 cigarettes or equivalent/day from the time of screening and throughout the period of sample collection;
* Health is judged to be stable based on medical history (except for the hepatic impairment condition), physical examination, vital signs, electrocardiogram (ECGs), and laboratory safety tests;
* For female participants of childbearing potential: either sexually inactive for 14 days prior to study start and throughout study or be using an acceptable birth control method;
* Female participants who are sexually inactive, but become sexually active during the course of the study must agree to use a double physical barrier method (e.g., condom and diaphragm) and a chemical barrier (e.g., spermicide) from the time of the start of sexual activity through completion of the study;
* Vasectomized or non-vasectomized male participants must agree to use a condom with spermicide or abstain from sexual intercourse from dosing until 90 days after dosing;
* Male participants must agree not to donate sperm from dosing until 90 days after dosing;
* Able to swallow multiple tablets and capsules.

Exclusion Criteria:

HI Participants Only:

* Presence of moderate or severe renal insufficiency (estimated glomerular filtration rate \[eGFR\] ≤50 mL/min/1.73 m\^2 calculated according to the Modification of Diet in Renal Disease \[MDRD\] study equation);
* Presence of drug abuse within the past 6 months prior to dosing.

Healthy Participants Only:

* Presence of moderate or severe renal insufficiency (eGFR ≤60 mL/min/1.73 m\^2 calculated according to the MDRD study equation);
* History or presence of alcoholism or drug abuse within the past 2 years prior to dosing;

All Participants:

* Is mentally or legally incapacitated or has significant emotional problems at the time of study start or expected during the study;
* History or presence of clinically significant medical or psychiatric condition or disease;
* History or presence of hypersensitivity or idiosyncratic reaction to the study drugs or related compounds;
* Female participants who are pregnant or lactating;
* Positive results at study start for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV);
* Unable to refrain from or anticipates the use of any medication or substance (including prescription or over-the-counter, vitamin supplements, natural or herbal supplements) for the prohibited time period;
* Has taken amiodarone at any time in their life;
* Donation of blood \>500 mL or had significant blood loss within 56 days prior to the dose of study drugs;
* Plasma donation within 7 days prior to the dose of study drugs;
* Dosed in another clinical trial within 28 days prior to dosing of study drugs;

Primary outcomes:
measure: Area Under the Drug Plasma Concentration-Time Curve From Start of Dosing to Time of the Last Quantifiable Sample (AUC0-last) of Uprifosbuvir
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: Area Under the Drug Plasma Concentration-Time Curve From Start of Dosing to Infinity (AUC0-inf) of Uprifosbuvir
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: Area Under the Plasma Drug Concentration-Time Curve From Start of Dosing to 24 Hours Post-Dose (AUC0-24hr) of Uprifosbuvir
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose
measure: Maximum Plasma Drug Concentration (Cmax) of Uprifosbuvir
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: Plasma Drug Concentration at 24 Hours (C24hr) of Uprifosbuvir
timeFrame: 24 hours post-dose
measure: Time to Reach Cmax (Tmax) of Uprifosbuvir
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: Apparent Terminal Half-Life (t1/2) of Uprifosbuvir
timeFrame: Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: Apparent Total Clearance From Plasma After Oral Administration (CL/F) of Uprifosbuvir
timeFrame: Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) of Uprifosbuvir
timeFrame: Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: AUC0-last of Uprifosbuvir Metabolite M5
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: AUC0-inf of Uprifosbuvir Metabolite M5
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: AUC0-24hr of Uprifosbuvir Metabolite M5
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose
measure: Cmax of Uprifosbuvir Metabolite M5
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: C24hr of Uprifosbuvir Metabolite M5
timeFrame: 24 hours post-dose
measure: Lag Time (Tlag) for Uprifosbuvir Metabolite M5
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: Tmax of Uprifosbuvir Metabolite M5
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: Apparent t1/2 of Uprifosbuvir Metabolite M5
timeFrame: Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: AUC0-last of Uprifosbuvir Metabolite M6
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: AUC0-inf of Uprifosbuvir Metabolite M6
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: AUC0-24hr of Uprifosbuvir Metabolite M6
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose
measure: Cmax of Uprifosbuvir Metabolite M6
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: C24hr of Uprifosbuvir Metabolite M6
timeFrame: 24 hours post-dose
measure: Tmax of Uprifosbuvir Metabolite M6
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: Apparent t1/2 of Uprifosbuvir Metabolite M6
timeFrame: Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: AUC0-last of Ruzasvir
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: AUC0-inf of Ruzasvir
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: AUC0-24hr of Ruzasvir
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose
measure: Maximum Plasma Drug Concentration (Cmax) of Ruzasvir
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: C24hr of Ruzasvir
timeFrame: 24 hours post-dose
measure: Tmax of Ruzasvir
timeFrame: Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: Apparent t1/2 of Ruzasvir
timeFrame: Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: CL/F of Ruzasvir
timeFrame: Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
measure: Vz/F of Ruzasvir
timeFrame: Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: