Phase 1
N=24
A Study of the Pharmacokinetics of Uprifosbuvir (MK-3682) and Ruzasvir (MK-8408) in Participants With Moderate and Severe Hepatic Insufficiency (MK-3682-029)
Hepatitis C, Chronic
Bottom Line
View on ClinicalTrials.gov: NCT02666352 ↗Enrolled (actual)
24
Serious AEs
0.0%
Results posted
Sep 2018
Primary outcome: Primary: Area Under the Drug Plasma Concentration-Time Curve From Start of Dosing to Time of the Last Quantifiable Sample (AUC0-last) of Uprifosbuvir — 5.34; 8.02; 3.74 µM*hr
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 1
- Interventions
- Uprifosbuvir (Drug); Ruzasvir (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Merck Sharp & Dohme LLC
- Primary completion
- Jan 2017
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Area Under the Drug Plasma Concentration-Time Curve From Start of Dosing to Time of the Last Quantifiable Sample (AUC0-last) of Uprifosbuvir |
5.34; 8.02; 3.74 | — |
| PRIMARY Area Under the Drug Plasma Concentration-Time Curve From Start of Dosing to Infinity (AUC0-inf) of Uprifosbuvir |
5.39; 8.09; 3.76 | — |
| PRIMARY Area Under the Plasma Drug Concentration-Time Curve From Start of Dosing to 24 Hours Post-Dose (AUC0-24hr) of Uprifosbuvir |
5.35; 8.02; 3.74 | — |
| PRIMARY Maximum Plasma Drug Concentration (Cmax) of Uprifosbuvir |
1560; 2130; 1180 | — |
| PRIMARY Plasma Drug Concentration at 24 Hours (C24hr) of Uprifosbuvir |
7.01; 8.56; 2.55 | — |
| PRIMARY Time to Reach Cmax (Tmax) of Uprifosbuvir |
1.00; 0.50; 1.25 | — |
| PRIMARY Apparent Terminal Half-Life (t1/2) of Uprifosbuvir |
3.66; 3.56; 3.17 | — |
| PRIMARY Apparent Total Clearance From Plasma After Oral Administration (CL/F) of Uprifosbuvir |
153; 102; 219 | — |
| PRIMARY Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) of Uprifosbuvir |
809; 524; 1000 | — |
| PRIMARY AUC0-last of Uprifosbuvir Metabolite M5 |
6.46; 6.79; 8.11 | — |
| PRIMARY AUC0-inf of Uprifosbuvir Metabolite M5 |
6.78; 7.22; 8.44 | — |
| PRIMARY AUC0-24hr of Uprifosbuvir Metabolite M5 |
2.41; 2.28; 3.12 | — |
| PRIMARY Cmax of Uprifosbuvir Metabolite M5 |
169; 151; 203 | — |
| PRIMARY C24hr of Uprifosbuvir Metabolite M5 |
124; 122; 150 | — |
| PRIMARY Lag Time (Tlag) for Uprifosbuvir Metabolite M5 |
3.00; 2.53; 2.00 | — |
| PRIMARY Tmax of Uprifosbuvir Metabolite M5 |
14.00; 16.00; 15.00 | — |
| PRIMARY Apparent t1/2 of Uprifosbuvir Metabolite M5 |
24.09; 25.64; 23.59 | — |
| PRIMARY AUC0-last of Uprifosbuvir Metabolite M6 |
28.6; 27.4; 41.8 | — |
| PRIMARY AUC0-inf of Uprifosbuvir Metabolite M6 |
30.1; 28.7; 47.0 | — |
| PRIMARY AUC0-24hr of Uprifosbuvir Metabolite M6 |
13.1; 13.2; 16.6 | — |
| PRIMARY Cmax of Uprifosbuvir Metabolite M6 |
851; 834; 1070 | — |
| PRIMARY C24hr of Uprifosbuvir Metabolite M6 |
402; 410; 564 | — |
| PRIMARY Tmax of Uprifosbuvir Metabolite M6 |
6.00; 4.00; 4.00 | — |
| PRIMARY Apparent t1/2 of Uprifosbuvir Metabolite M6 |
26.96; 26.45; 33.98 | — |
| PRIMARY AUC0-last of Ruzasvir |
2.30; 2.70; 1.98 | — |
| PRIMARY AUC0-inf of Ruzasvir |
2.60; 3.32; 2.10 | — |
| PRIMARY AUC0-24hr of Ruzasvir |
1.04; 1.05; 1.17 | — |
| PRIMARY Maximum Plasma Drug Concentration (Cmax) of Ruzasvir |
105; 92.5; 137 | — |
| PRIMARY C24hr of Ruzasvir |
27.6; 32.4; 23.0 | — |
| PRIMARY Tmax of Ruzasvir |
3.00; 2.03; 3.00 | — |
| PRIMARY Apparent t1/2 of Ruzasvir |
38.08; 47.26; 30.43 | — |
| PRIMARY CL/F of Ruzasvir |
28.4; 20.6; 32.6 | — |
| PRIMARY Vz/F of Ruzasvir |
1560; 1400; 1430 | — |
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;
Data sourced from ClinicalTrials.gov (NCT02666352). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.