Pharmacokinetics of MK-3682B in Participants With Moderate to Severe Renal Insufficiency (MK-3682B-030)

NCT02661126 | Completed Phase 1 Results

• 3 other identifiers: 3682B-030MK-3682B-030CA16919
• Study Type: interventional
• Target: 16
• Locations: 0 countries
• Sites: N/A

Brief Summary

The purpose of this study is to compare the plasma pharmacokinetics (PK) of single doses of MK-3682B, a fixed dose combination (FDC) tablet containing uprifosbuvir (MK-3682) + grazoprevir (MK-5172) + ruzasvir (MK-8408) in participants with moderate (Part 1) and severe (Part 2) renal insufficiency (RI) to plasma PK in healthy participants.

Conditions

Hepatitis C

Outcome Measures

Primary Outcomes (42)

• Area Under the Plasma Concentration-time Curve (AUC) From Dosing to Time of Last Measurable Concentration (AUC0-last) of Uprifosbuvir (MK-3682)

  AUC0-last is a measure of total exposure to uprifosbuvir in plasma from the start of dosing to the time of the last quantifiable (\< lower limit of quantification \[LLOQ\]) sample following oral administration of MK-3682B.

  0 (pre-dose), 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

• AUC From Dosing to Infinity (AUC0-∞) of Uprifosbuvir

  AUC0-∞ is a measure of total exposure to uprifosbuvir in plasma from the start of dosing to infinity following oral administration of MK-3682B.

  0 (pre-dose), 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

• AUC From Dosing to 24 Hours Post-dose (AUC0-24) of Uprifosbuvir

  AUC0-24 is a measure of total exposure to uprifosbuvir in plasma from dosing to 24 hours following oral administration of MK-3682B.

  0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose

• Maximum Plasma Concentration (Cmax) of Uprifosbuvir

  Cmax is the maximum amount of uprifosbuvir in plasma following oral administration of MK-3682B.

  0 (pre-dose), 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

• Plasma Concentration 24 Hours Post-dose (C24) of Uprifosbuvir

  C24 is the plasma concentration of uprifosbuvir 24 hours following oral administration of MK-3682B.

  24 hours post-dose

• Time to Reach Maximum Plasma Concentration (Tmax) of Uprifosbuvir

  Tmax is the time required to reach the maximum post-dose plasma concentration of uprifosbuvir following oral administration of MK-3682B.

  0 (pre-dose), 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 Total Body Clearance (CL/F) of Uprifosbuvir

  CL/F is the apparent total body clearance of uprifosbuvir following oral administration of MK-3682B.

  0 (pre-dose), 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 Volume of Distribution (Vz/F) of Uprifosbuvir

  Vz/F is the apparent volume of distribution of uprifosbuvir following oral administration of MK-3682B.

  0 (pre-dose), 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 Terminal Half-life in Plasma (t½) of Uprifosbuvir

  t1/2 is the amount of time required to clear 50% of uprifosbuvir from plasma following oral administration of MK-3682B.

  0 (pre-dose), 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 of Uprifosbuvir Metabolite M5

  AUC0-last is a measure of total exposure to uprifosbuvir metabolite M5 in plasma from the start of dosing to the time of the last quantifiable (\<LLOQ) sample following oral administration of MK-3682B.

  0 (pre-dose), 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-∞ of Uprifosbuvir Metabolite M5

  AUC0-∞ is a measure of total exposure to uprifosbuvir metabolite M5 in plasma from the start of dosing to infinity following oral administration of MK-3682B.

  0 (pre-dose), 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

• AUC0-24 of Uprifosbuvir Metabolite M5

  AUC0-24 is a measure of total exposure to uprifosbuvir metabolite M5 in plasma from dosing to 24 hours following oral administration of MK-3682B.

  0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose

• Cmax of Uprifosbuvir Metabolite M5

  Cmax is the maximum amount of uprifosbuvir metabolite M5 in plasma following oral administration of MK-3682B.

  0 (pre-dose), 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

• C24 of Uprifosbuvir Metabolite M5

  C24 is the plasma concentration of uprifosbuvir metabolite M5 24 hours following oral administration of MK-3682B.

  24 hours post-dose

• Tmax of Uprifosbuvir Metabolite M5

  Tmax is the time required to reach the maximum post-dose plasma concentration of uprifosbuvir metabolite M5 following oral administration of MK-3682B.

  0 (pre-dose), 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

• Lag Time (Tlag) of Uprifosbuvir Metabolite M5

  Tlag is the time from dosing to first appearance in plasma of uprifosbuvir metabolite M5 following oral administration of MK-3682B.

  0 (pre-dose), 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

• t½ of Uprifosbuvir Metabolite M5

  t1/2 is the amount of time required to clear 50% of uprifosbuvir metabolite M5 from plasma following oral administration of MK-3682B.

  0 (pre-dose), 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 of Uprifosbuvir Metabolite M6

  AUC0-last is a measure of total exposure to uprifosbuvir metabolite M6 in plasma from the start of dosing to the time of the last quantifiable (\<LLOQ) sample following oral administration of MK-3682B.

  0 (pre-dose), 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-∞ of Uprifosbuvir Metabolite M6

  AUC0-∞ is a measure of total exposure to uprifosbuvir metabolite M6 in plasma from the start of dosing to infinity following oral administration of MK-3682B.

  0 (pre-dose), 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

• AUC0-24 of Uprifosbuvir Metabolite M6

  AUC0-24 is a measure of total exposure to uprifosbuvir metabolite M6 in plasma from dosing to 24 hours following oral administration of MK-3682B.

  0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose

• Cmax of Uprifosbuvir Metabolite M6

  Cmax is the maximum amount of uprifosbuvir metabolite M6 in plasma following oral administration of MK-3682B.

  0 (pre-dose), 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

• C24 of Uprifosbuvir Metabolite M6

  C24 is the plasma concentration of uprifosbuvir metabolite M6 24 hours following oral administration of MK-3682B.

  24 hours post-dose

• Tmax of Uprifosbuvir Metabolite M6

  Tmax is the time required to reach the maximum post-dose plasma concentration of uprifosbuvir metabolite M6 following oral administration of MK-3682B.

  0 (pre-dose), 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

• t½ of Uprifosbuvir Metabolite M6

  t1/2 is the amount of time required to clear 50% of uprifosbuvir metabolite M6 from plasma following oral administration of MK-3682B.

  0 (pre-dose), 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 of Grazoprevir (MK-5172)

  AUC0-last is a measure of total exposure to grazoprevir in plasma from the start of dosing to the time of the last quantifiable (\<LLOQ) sample following oral administration of MK-3682B.

  0 (pre-dose), 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-∞ of Grazoprevir

  AUC0-∞ is a measure of total exposure to grazoprevir in plasma from the start of dosing to infinity following oral administration of MK-3682B.

  0 (pre-dose), 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

• AUC0-24 of Grazoprevir

  AUC0-24 is a measure of total exposure to grazoprevir in plasma from the start of dosing to 24 hours post-dose following oral administration of MK-3682B.

  0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose

• Cmax of Grazoprevir

  Cmax is the maximum amount of grazoprevir in plasma following oral administration of MK-3682B.

  0 (pre-dose), 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

• C24 of Grazoprevir

  C24 is the plasma concentration of grazoprevir 24 hours following oral administration of MK-3682B.

  24 hours post-dose

• Tmax of Grazoprevir

  Tmax is the time required to reach the maximum post-dose plasma concentration of grazoprevir following oral administration of MK-3682B.

  0 (pre-dose), 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 of Grazoprevir

  CL/F is the apparent total body clearance of grazoprevir following oral administration of MK-3682B.

  0 (pre-dose), 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 of Grazoprevir

  Vz/F is the apparent volume of distribution of grazoprevir following oral administration of MK-3682B.

  0 (pre-dose), 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

• t½ of Grazoprevir

  t1/2 is the amount of time required to clear 50% of grazoprevir from plasma following oral administration of MK-3682B.

  0 (pre-dose), 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 of Ruzasvir (MK-8408)

  AUC0-last is a measure of total exposure to ruzasvir in plasma from the start of dosing to the time of the last quantifiable (\<LLOQ) sample following oral administration of MK-3682B.

  0 (pre-dose), 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-∞ of Ruzasvir

  AUC0-∞ is a measure of total exposure to ruzasvir in plasma from the start of dosing to infinity following oral administration of MK-3682B.

  0 (pre-dose), 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

• AUC0-24 of Ruzasvir

  AUC0-24 is a measure of total exposure to ruzasvir in plasma from dosing to 24 hours following oral administration of MK-3682B.

  0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose

• Cmax of Ruzasvir

  Cmax is the maximum amount of ruzasvir in plasma following oral administration of MK-3682B.

  0 (pre-dose), 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

• C24 of Ruzasvir

  C24 is the plasma concentration of ruzasvir 24 hours following oral administration of MK-3682B.

  24 hours post-dose

• Tmax of Ruzasvir

  Tmax is the time required to reach the maximum post-dose plasma concentration of ruzasvir following oral administration of MK-3682B.

  0 (pre-dose), 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 of Ruzasvir

  CL/F is the apparent total body clearance of ruzasvir following oral administration of MK-3682B.

  0 (pre-dose), 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 of Ruzasvir

  Vz/F is the apparent volume of distribution of ruzasvir following oral administration of MK-3682B.

  0 (pre-dose), 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

• t½ of Ruzasvir

  t1/2 is the amount of time required to clear 50% of ruzasvir from plasma following oral administration of MK-3682B.

  0 (pre-dose), 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

Study Arms (3)

Moderate RI Participants

EXPERIMENTAL

Participants with an estimated glomerular filtration rate (eGFR) of ≥30 mL/min/1.73m\^2 to \<60 mL/min/1.73m\^2 take 2 MK-3682B FDC tablets on Day 1 after fasting for 10 hours.

Drug: MK-3682B

Severe RI Participants

EXPERIMENTAL

Participants with an eGFR of ≥15 mL/min/1.73m\^2 to \<30 mL/min/1.73m\^2 take 2 MK-3682B FDC tablets on Day 1 after fasting for 10 hours.

Drug: MK-3682B

Healthy Participants

EXPERIMENTAL

Healthy participants (creatinine clearance \[CLcr\] ≥80 mL/min) take 2 MK-362B FDC tablets on Day 1 after fasting for 10 hours. Healthy participants are matched to RI participants based on mean age, body mass index (BMI) and gender.

Drug: MK-3682B

Interventions

MK-3682B DRUG

FDC oral tablet containing 225 mg uprifosbuvir + 50 mg grazoprevir + 30 mg ruzasvir.

Healthy Participants; Moderate RI Participants; Severe RI Participants

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All Participants:
• Healthy adult males or females 18-80 years of age at screening
• Continuous non-smokers or moderate smokers (≤ 20 cigarettes/day or the equivalent) and agrees to consume no more than 10 cigarettes per day during the study period
• BMI ≥ 18 and ≤ 40.0 kg/m\^2
• Agrees not to become pregnant or father a child during participation in the study
• Females of childbearing potential must either be abstinent for 14 days prior to dosing and throughout the study or be using an acceptable birth control method
• Vasectomized or non-vasectomized males must agree to use a condom with spermicide or abstain from sexual intercourse from the first dose until 90 days after dosing
• Males must agree not to donate sperm from dosing until 90 days after dosing
• Moderate and Severe RI Participants:
• Baseline health is judged to be stable based on medical history, physical examination, laboratory profiles, vital signs, or electrocardiograms (ECGs), as deemed by the Investigator
• Has had no clinically significant change in renal status at least 1 month prior to dosing and is not currently or has not previously been on hemodialysis
• Moderate RI: has baseline eGFR ≥ 30 mL/min/1.73m\^2 and \< 60 mL/min/1.73m\^2, based on the Modification of Diet in Renal Disease (MDRD) equation at screening
• Severe RI: has baseline eGFR ≥ 15 mL/min/1.73m\^2 and \< 30 mL/min/1.73m\^2, based on the MDRD equation at screening
• Healthy Participants:
• Is within ± 10 years of the mean age of moderate and severe RI arms

You may not qualify if:

• Is mentally or legally incapacitated or has significant emotional problems at the time of the screening
• History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the Investigator
• History of any illness that, in the opinion of the Investigator, might confound the results of the study or poses an additional risk by participating in the study
• Is female and pregnant or lactating
• Positive results for the urine or saliva drug screen or urine or breath alcohol screen at screening or check-in unless the positive drug screen is due to prescription drug use that is approved by the Investigator and Sponsor
• Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV)
• Seated heart rate is equal to or lower than 44 beats per minute (bpm) or higher than 100 bpm at screening
• Has had a renal transplant or has had nephrectomy
• Donation of blood or had significant blood loss within 56 days prior to dosing of study drug, or donation of plasma within 7 days prior to dosing
• Has participated in another clinical trial within 28 days prior to dosing of study drug

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

MeSH Terms

Conditions

Hepatitis C

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis; Liver Diseases; Digestive System Diseases

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 19, 2016
• First Posted: January 22, 2016
• Study Start: January 19, 2016
• Primary Completion: August 26, 2016
• Study Completion: August 26, 2016
• Last Updated: January 9, 2019
• Results First Posted: December 14, 2018

Record last verified: 2018-12

Data Sharing

• IPD Sharing: Will share