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 Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02666352
• Other study ID #: 3682-029
• Status: Completed
• Phase: Phase 1
• Start date: January 22, 2016
• Est. completion date: January 16, 2017

Study information

• Verified date: January 2018
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: January 16, 2017
• Est. primary completion date: January 16, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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;

Related Conditions & MeSH terms

• Hepatic Insufficiency
• Hepatitis C
• Hepatitis C, Chronic

Intervention

Drug:
• Uprifosbuvir
A single dose of uprifosbuvir 450 mg (given as three 150-mg tablets) taken by mouth.
• Ruzasvir
A single dose of ruzasvir 60 mg (given as six 10-mg capsules) taken by mouth.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Drug Plasma Concentration-Time Curve From Start of Dosing to Time of the Last Quantifiable Sample (AUC0-last) of Uprifosbuvir	AUC0-last is a measure of the mean plasma drug concentration from time of dosing to the last quantifiable sample. The AUC0-last for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	Area Under the Drug Plasma Concentration-Time Curve From Start of Dosing to Infinity (AUC0-inf) of Uprifosbuvir	AUC0-inf is a measure of the mean plasma drug concentration from time of dosing to infinity. The AUC0-inf for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	Area Under the Plasma Drug Concentration-Time Curve From Start of Dosing to 24 Hours Post-Dose (AUC0-24hr) of Uprifosbuvir	AUC0-24hr is a measure of the mean plasma drug concentration from time of dosing to 24 hours post-dose. The AUC0-24hr for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	Maximum Plasma Drug Concentration (Cmax) of Uprifosbuvir	Cmax is the maximum observed plasma drug concentration after dosing. The Cmax for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	Plasma Drug Concentration at 24 Hours (C24hr) of Uprifosbuvir	C24hr is a measure of plasma drug concentration 24 hours after dosing. The C24hr of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	24 hours post-dose
Primary	Time to Reach Cmax (Tmax) of Uprifosbuvir	Tmax is the time required to reach maximum plasma drug concentration (i.e., Cmax). The Tmax for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	Apparent Terminal Half-Life (t1/2) of Uprifosbuvir	t1/2 is a measure of how long it takes to clear 50% of drug after reaching Cmax. The t1/2 for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	Apparent Total Clearance From Plasma After Oral Administration (CL/F) of Uprifosbuvir	CL/F is a measure of the apparent rate at which drug is removed from the body via renal, hepatic, and other clearance pathways after oral administration. The CL/F of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) of Uprifosbuvir	Vz/F is the apparent volume of distribution during the terminal phase after non-intravenous administration. The Vz/F of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	AUC0-last of Uprifosbuvir Metabolite M5	AUC0-last is a measure of the mean plasma drug concentration from time of dosing to the last quantifiable sample. The AUC0-last for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	AUC0-inf of Uprifosbuvir Metabolite M5	AUC0-inf is a measure of the mean plasma drug concentration from time of dosing to infinity. The AUC0-inf for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	AUC0-24hr of Uprifosbuvir Metabolite M5	AUC0-24hr is a measure of the mean plasma drug concentration from time of dosing to 24 hours post-dose. The AUC0-24hr for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	Cmax of Uprifosbuvir Metabolite M5	Cmax is the maximum observed plasma drug concentration after dosing. The Cmax for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	C24hr of Uprifosbuvir Metabolite M5	C24hr is a measure of plasma drug concentration 24 hours after dosing. The C24hr of the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	24 hours post-dose
Primary	Lag Time (Tlag) for Uprifosbuvir Metabolite M5	Tlag is a measure of the time delay between drug administration and the onset of absorption, where onset of absorption is defined as "the time point prior to the first observed/measured non-zero plasma concentration". The Tlag of the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm (in this study Tlag was only calculated for the M5 uprifosbuvir metabolite).	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
Primary	Tmax of Uprifosbuvir Metabolite M5	Tmax is the time required to reach maximum plasma drug concentration (i.e., Cmax). The Tmax for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	Apparent t1/2 of Uprifosbuvir Metabolite M5	Apparent t1/2 is a measure of how long it takes to clear 50% of drug after reaching Cmax. The t1/2 for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	AUC0-last of Uprifosbuvir Metabolite M6	AUC0-last is a measure of the mean plasma drug concentration from time of dosing to the last quantifiable sample. The AUC0-last for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	AUC0-inf of Uprifosbuvir Metabolite M6	AUC0-inf is a measure of the mean plasma drug concentration from time of dosing to infinity. The AUC0-inf for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	AUC0-24hr of Uprifosbuvir Metabolite M6	AUC0-24hr is a measure of the mean plasma drug concentration from time of dosing to 24 hours post-dose. The AUC0-24hr for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	Cmax of Uprifosbuvir Metabolite M6	Cmax is the maximum observed plasma drug concentration after dosing. The Cmax for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	C24hr of Uprifosbuvir Metabolite M6	C24hr is a measure of plasma drug concentration 24 hours after dosing. The C24hr of the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	24 hours post-dose
Primary	Tmax of Uprifosbuvir Metabolite M6	Tmax is the time required to reach maximum plasma drug concentration (i.e., Cmax). The Tmax for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	Apparent t1/2 of Uprifosbuvir Metabolite M6	Apparent t1/2 is a measure of how long it takes to clear 50% of drug after reaching Cmax. The t1/2 for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.	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
Primary	AUC0-last of Ruzasvir	AUC0-last is a measure of the mean plasma drug concentration from time of dosing to the last quantifiable sample. The AUC0-last for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.	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
Primary	AUC0-inf of Ruzasvir	AUC0-inf is a measure of the mean plasma drug concentration from time of dosing to infinity. The AUC0-inf for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.	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
Primary	AUC0-24hr of Ruzasvir	AUC0-24hr is a measure of the mean plasma drug concentration from time of dosing to 24 hours post-dose. The AUC0-24hr for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.	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
Primary	Maximum Plasma Drug Concentration (Cmax) of Ruzasvir	Cmax is the maximum observed plasma drug concentration after dosing. The Cmax for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.	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
Primary	C24hr of Ruzasvir	C24hr is a measure of plasma drug concentration 24 hours after dosing. The C24hr of ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.	24 hours post-dose
Primary	Tmax of Ruzasvir	Tmax is the time required to reach maximum plasma drug concentration (i.e., Cmax). The Tmax of ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.	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
Primary	Apparent t1/2 of Ruzasvir	Apparent t1/2 is a measure of how long it takes to clear 50% of drug after reaching Cmax. The t1/2 for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.	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
Primary	CL/F of Ruzasvir	CL/F is a measure of the apparent rate at which drug is removed from the body via renal, hepatic, and other clearance pathways after oral administration. The CL/F of ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.	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
Primary	Vz/F of Ruzasvir	Vz/F is the apparent volume of distribution during the terminal phase after non-intravenous administration. The Vz/F of ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.	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