Study to Investigate the Influence of Hepatic Insufficiency on the Pharmacokinetics of Grazoprevir (MK-5172-013)

NCT01390428 | Completed Phase 1 Results

• 1 other identifier: 5172-013
• Study Type: interventional
• Target: 50
• Locations: 0 countries
• Sites: N/A

Brief Summary

This study will compare the pharmacokinetics (PK) of grazoprevir (MK-5172) when administered to participants with mild, moderate or severe hepatic insufficiency (assessed by the criteria of the Child-Pugh's scale) with the PK of grazoprevir when administered to healthy participants.

Conditions

Hepatitis C

Outcome Measures

Primary Outcomes (7)

• Area Under the Concentration Time-curve From 0 to 24 Hours (AUC0-24) of Grazoprevir

  Blood samples were collected at pre-dose, and from 0.5 to 24 hours post-dose on Days 1 and 10 in order to determine the plasma AUC0-24 of Grazoprevir. Classification of HI based on the Child-Pugh scale, where a score of 5-6 = Mild HI; a score of 7-9 = Moderate HI; and a score of 10-15 = Severe HI.

  Days 1 and 10 at the following timepoints: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose

• Maximum Concentration (Cmax) of Grazoprevir

  Blood samples were collected at pre-dose, and from 0.5 to 24 hours post-dose on Days 1 and 10 in order to determine the plasma Cmax of Grazoprevir. Classification of HI based on the Child-Pugh scale, where a score of 5-6 = Mild HI; a score of 7-9 = Moderate HI; and a score of 10-15 = Severe HI.

  Days 1 and 10 at the following timepoints: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose

• Time to Peak Concentration (Tmax) of Grazoprevir

  Blood samples were collected at pre-dose, and from 0.5 to 24 hours post-dose on Days 1 and 10 in order to determine the plasma Tmax of Grazoprevir. Classification of HI based on the Child-Pugh scale, where a score of 5-6 = Mild HI; a score of 7-9 = Moderate HI; and a score of 10-15 = Severe HI.

  Days 1 and 10 at the following timepoints: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose

• Concentrations 24 Hours Post-dose (C24) of Grazoprevir on Day 1 for Participants With Mild HI and Moderate HI and Healthy Matched to Mild HI and Moderate HI

  Blood samples were collected at 24 hours post-dose on Day 1 in order to determine the plasma C24 of Grazoprevir. Classification of HI based on the Child-Pugh scale, where a score of 5-6 = Mild HI; a score of 7-9 = Moderate HI; and a score of 10-15 = Severe HI.

  Day 1 at 24 hours postdose

• Concentrations 24 Hours Post-dose (C24) of Grazoprevir on Day 1 for Participants With Severe HI and Healthy Matched to Severe HI

  Blood samples were collected at 24 hours post-dose on Day 1 in order to determine the plasma C24 of Grazoprevir. Classification of HI based on the Child-Pugh scale, where a score of 5-6 = Mild HI; a score of 7-9 = Moderate HI; and a score of 10-15 = Severe HI.

  Day 1 at 24 hours postdose

• Concentrations 24 Hours Post-dose (C24) of Grazoprevir on Day 10

  Blood samples were collected at 24 hours post-dose on Day 10 in order to determine the plasma C24 of Grazoprevir. Classification of HI based on the Child-Pugh scale, where a score of 5-6 = Mild HI; a score of 7-9 = Moderate HI; and a score of 10-15 = Severe HI.

  Days 10 at 24 hours postdose

• Apparent Terminal Half-life (t1/2) of Grazoprevir

  Blood samples were collected at pre-dose, and from 0.5 to 24 hours post-dose on Day 10 in order to determine the plasma t1/2 of Grazoprevir. Classification of HI based on the Child-Pugh scale, where a score of 5-6 = Mild HI; a score of 7-9 = Moderate HI; and a score of 10-15 = Severe HI.

  Day 10 at the following timepoints: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 hours post-dose

Study Arms (6)

Part 1-Mild Hepatic Impairment (HI)

EXPERIMENTAL

Participants with mild hepatic impairment will receive 200 mg of Grazoprevir once a day for 10 consecutive days during Part 1 of the study.

Drug: Grazoprevir

Part 1-Healthy Matched to Mild HI

EXPERIMENTAL

Healthy participants will receive 200 mg of Grazoprevir once a day for 10 consecutive days during Part 1 of the study.

Drug: Grazoprevir

Part 2-Moderate HI

EXPERIMENTAL

Participants with moderate hepatic impairment will receive 100 mg of Grazoprevir once a day for 10 consecutive days during Part 2 of the study.

Drug: Grazoprevir

Part 2-Healthy Matched to Moderate HI

EXPERIMENTAL

Healthy participants will receive 100 mg of Grazoprevir once a day for 10 consecutive days during Part 2 of the study.

Drug: Grazoprevir

Part 3-Severe HI

EXPERIMENTAL

Participants with severe hepatic impairment will receive 50 mg of Grazoprevir once a day for 10 consecutive days during Part 3 of the study.

Drug: Grazoprevir

Part 3-Healthy Matched to Severe HI

EXPERIMENTAL

Healthy participants will receive 50 mg of Grazoprevir once a day for 10 consecutive days during Part 3 of the study.

Drug: Grazoprevir

Interventions

Grazoprevir DRUG

Part 1: oral morning dose of 200 mg daily for 10 days Part 2: oral morning dose of 100 mg daily for 10 days Part 3: oral morning dose of 50 mg daily for 10 days

Part 1-Healthy Matched to Mild HI; Part 1-Mild Hepatic Impairment (HI); Part 2-Healthy Matched to Moderate HI; Part 2-Moderate HI; Part 3-Healthy Matched to Severe HI; Part 3-Severe HI

Eligibility Criteria

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

You may qualify if:

• If female, must be of non-childbearing potential or willing to use at least 2 acceptable methods of contraception from enrollment to 2 weeks after the last dose of study drug
• No clinically significant abnormality on electrocardiogram
• Hepatic Insufficiency Participants Only:
• Other than hepatic insufficiency with features of cirrhosis, is otherwise in good health based on medical history, physical examination, vital signs, and laboratory safety tests
• Chronic (\>6 months), stable (no acute episodes of illness within the previous 2 months due to deterioration in hepatic function) hepatic insufficiency with features of cirrhosis due to any etiology
• Score on the Child-Pugh scale must range from 5 to 6 (mild hepatic insufficiency) to from 7 to 9 (moderate hepatic insufficiency) to from 10 to 15 (severe hepatic insufficiency)
• Matched Healthy Participants Only:
• \- In good health based on medical history, physical examination, vital signs, and laboratory safety tests

You may not qualify if:

• History of any illness that might confound the results of the study or poses an additional risk to the participant
• History of clinically significant endocrine, gastrointestinal (other than related to their hepatic impairment), cardiovascular, hematological, immunological, renal, respiratory, or genitourinary abnormalities or diseases
• Pregnancy
• Estimated creatinine clearance of ≤60 mL/min
• History of stroke, chronic seizures, or major neurological disorder
• History of neoplastic disease (including leukemia, lymphoma, malignant melanoma), or myeloproliferative disease, regardless of the time since treatment
• Unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies (such as St. John's Wort, green tea, gingko, coenzyme Q, ginseng, echinacea, etc.) or nutritional supplements (e.g., garlic supplements), beginning approximately 2 weeks (or 5 half-lives) prior to administration of the initial dose of study drug, throughout the study, until the poststudy visit
• Participated in another investigational study within 4 weeks
• History of significant multiple and/or severe allergies or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food
• Hepatic Insufficiency Participants Only:
• \- Has a history of hepatitis C infection by serology, regardless of most recent viral load status.
• Matched Healthy Participants Only:
• History of any chronic and/or active hepatic disease including elevations of serum transaminases, hepatitis, biliary tract disease, or a history of any significant gastrointestinal surgery.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (1)

• Caro L, Wenning L, Guo Z, Fraser IP, Fandozzi C, Talaty J, Panebianco D, Ho M, Uemura N, Reitmann C, Angus P, Gane E, Marbury T, Smith WB, Iwamoto M, Butterton JR, Yeh WW. Effect of Hepatic Impairment on the Pharmacokinetics of Grazoprevir, a Hepatitis C Virus Protease Inhibitor. Antimicrob Agents Chemother. 2017 Nov 22;61(12):e00813-17. doi: 10.1128/AAC.00813-17. Print 2017 Dec.

  PMID: 28947470 RESULT

MeSH Terms

Conditions

Hepatitis C

Interventions

grazoprevir

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
• Restriction Type: OTHER
• Restrictive Agreement: Yes

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: July 7, 2011
• First Posted: July 11, 2011
• Study Start: July 28, 2011
• Primary Completion: September 5, 2014
• Study Completion: September 12, 2014
• Last Updated: September 14, 2018
• Results First Posted: March 4, 2016

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will share