Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Help guide our efforts to modernize ClinicalTrials.gov.
Send us your comments by March 14, 2020.

A Study of the Pharmacokinetics of Uprifosbuvir (MK-3682) and Ruzasvir (MK-8408) in Participants With Moderate and Severe Hepatic Insufficiency (MK-3682-029)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02666352
Recruitment Status : Completed
First Posted : January 28, 2016
Results First Posted : September 17, 2018
Last Update Posted : September 17, 2018
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

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.

Condition or disease Intervention/treatment Phase
Hepatitis C, Chronic Drug: Uprifosbuvir Drug: Ruzasvir Phase 1

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : January 22, 2016
Actual Primary Completion Date : January 16, 2017
Actual Study Completion Date : January 16, 2017

Arm Intervention/treatment
Experimental: Moderate HI Participants
On Day 1, participants with moderate HI will receive a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Drug: Uprifosbuvir
A single dose of uprifosbuvir 450 mg (given as three 150-mg tablets) taken by mouth.
Other Name: MK-3682

Drug: Ruzasvir
A single dose of ruzasvir 60 mg (given as six 10-mg capsules) taken by mouth.
Other Name: MK-8408

Experimental: Severe HI Participants
On Day 1, participants with severe HI will receive a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Drug: Uprifosbuvir
A single dose of uprifosbuvir 450 mg (given as three 150-mg tablets) taken by mouth.
Other Name: MK-3682

Drug: Ruzasvir
A single dose of ruzasvir 60 mg (given as six 10-mg capsules) taken by mouth.
Other Name: MK-8408

Experimental: Healthy Participants
On Day 1, participants with normal hepatic function will receive a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Drug: Uprifosbuvir
A single dose of uprifosbuvir 450 mg (given as three 150-mg tablets) taken by mouth.
Other Name: MK-3682

Drug: Ruzasvir
A single dose of ruzasvir 60 mg (given as six 10-mg capsules) taken by mouth.
Other Name: MK-8408




Primary Outcome Measures :
  1. Area Under the Drug Plasma Concentration-Time Curve From Start of Dosing to Time of the Last Quantifiable Sample (AUC0-last) of Uprifosbuvir [ Time Frame: 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 ]
    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.

  2. Area Under the Drug Plasma Concentration-Time Curve From Start of Dosing to Infinity (AUC0-inf) of Uprifosbuvir [ Time Frame: 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 ]
    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.

  3. Area Under the Plasma Drug Concentration-Time Curve From Start of Dosing to 24 Hours Post-Dose (AUC0-24hr) of Uprifosbuvir [ Time Frame: 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 ]
    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.

  4. Maximum Plasma Drug Concentration (Cmax) of Uprifosbuvir [ Time Frame: 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 ]
    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.

  5. Plasma Drug Concentration at 24 Hours (C24hr) of Uprifosbuvir [ Time Frame: 24 hours post-dose ]
    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.

  6. Time to Reach Cmax (Tmax) of Uprifosbuvir [ Time Frame: 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 ]
    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.

  7. Apparent Terminal Half-Life (t1/2) of Uprifosbuvir [ Time Frame: 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 ]
    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.

  8. Apparent Total Clearance From Plasma After Oral Administration (CL/F) of Uprifosbuvir [ Time Frame: 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 ]
    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.

  9. Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) of Uprifosbuvir [ Time Frame: 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 ]
    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.

  10. AUC0-last of Uprifosbuvir Metabolite M5 [ Time Frame: 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 ]
    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.

  11. AUC0-inf of Uprifosbuvir Metabolite M5 [ Time Frame: 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 ]
    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.

  12. AUC0-24hr of Uprifosbuvir Metabolite M5 [ Time Frame: 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 ]
    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.

  13. Cmax of Uprifosbuvir Metabolite M5 [ Time Frame: 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 ]
    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.

  14. C24hr of Uprifosbuvir Metabolite M5 [ Time Frame: 24 hours post-dose ]
    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.

  15. Lag Time (Tlag) for Uprifosbuvir Metabolite M5 [ Time Frame: 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 ]
    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).

  16. Tmax of Uprifosbuvir Metabolite M5 [ Time Frame: 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 ]
    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.

  17. Apparent t1/2 of Uprifosbuvir Metabolite M5 [ Time Frame: 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 ]
    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.

  18. AUC0-last of Uprifosbuvir Metabolite M6 [ Time Frame: 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 ]
    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.

  19. AUC0-inf of Uprifosbuvir Metabolite M6 [ Time Frame: 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 ]
    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.

  20. AUC0-24hr of Uprifosbuvir Metabolite M6 [ Time Frame: 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 ]
    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.

  21. Cmax of Uprifosbuvir Metabolite M6 [ Time Frame: 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 ]
    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.

  22. C24hr of Uprifosbuvir Metabolite M6 [ Time Frame: 24 hours post-dose ]
    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.

  23. Tmax of Uprifosbuvir Metabolite M6 [ Time Frame: 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 ]
    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.

  24. Apparent t1/2 of Uprifosbuvir Metabolite M6 [ Time Frame: 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 ]
    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.

  25. AUC0-last of Ruzasvir [ Time Frame: 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 ]
    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.

  26. AUC0-inf of Ruzasvir [ Time Frame: 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 ]
    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.

  27. AUC0-24hr of Ruzasvir [ Time Frame: 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 ]
    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.

  28. Maximum Plasma Drug Concentration (Cmax) of Ruzasvir [ Time Frame: 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 ]
    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.

  29. C24hr of Ruzasvir [ Time Frame: 24 hours post-dose ]
    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.

  30. Tmax of Ruzasvir [ Time Frame: 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 ]
    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.

  31. Apparent t1/2 of Ruzasvir [ Time Frame: 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 ]
    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.

  32. CL/F of Ruzasvir [ Time Frame: 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 ]
    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.

  33. Vz/F of Ruzasvir [ Time Frame: 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 ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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;

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02666352


Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Layout table for investigator information
Study Director: Medical Director Merck Sharp & Dohme Corp.

Layout table for additonal information
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT02666352    
Other Study ID Numbers: 3682-029
First Posted: January 28, 2016    Key Record Dates
Results First Posted: September 17, 2018
Last Update Posted: September 17, 2018
Last Verified: January 2018
Additional relevant MeSH terms:
Layout table for MeSH terms
Hepatitis C
Hepatitis C, Chronic
Hepatic Insufficiency
Liver Failure
Hepatitis
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Flaviviridae Infections
RNA Virus Infections
Hepatitis, Chronic
Uprifosbuvir
Ruzasvir
Antiviral Agents
Anti-Infective Agents