A Multiple Dose Study of Grazoprevir (MK-5172) in Hepatitis C-Infected Participants (MK-5172-010)

Study Overview
=================
Brief Summary
-----------------
The goal of this study was to compare hepatic pharmacokinetics (PK) derived from liver tissue to plasma PK after administration of grazoprevir (MK-5172) to participants with chronic hepatitis C virus (HCV) infection. Participants will be randomized to one of four different liver ultrasound-guided Fine Needle Aspirate (FNA) schedules (at 4-, 8-, 24-, or 72-hours after the Day 7 dose).

Official Title
-----------------
A Multiple Dose Study to Evaluate Pharmacokinetics and Hepatitis C Virus RNA Dynamics Following Administration of MK-5172 in Hepatitis C Infected Patients

Conditions
-----------------
Hepatitis C

Intervention / Treatment
-----------------
* Drug: Grazoprevir


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: has a Body Mass Index (BMI) ≥18.5 kg/m² and ≤36.0 kg/m² has chronic compensated, genotype 1 HCV infection has no cirrhosis of the liver as confirmed by FibroSure®/Fibro Test® and/or local country procedure (e.g. transient elastography/Fibroscan) does not require anticoagulants, nonsteroidal anti-inflammatory agents, and aspirin for at least fourteen (14) days preceding the initial liver biopsy and continuing throughout the entire study if is a female participant of reproductive potential, is willing to use 2 medically acceptable forms of contraception for 2 weeks prior to start of treatment through 2 weeks after last study treatment if is a male participant with a partner(s) of reproductive potential, is willing to use 2 medically acceptable forms of contraception from first dose to 90 days after last dose Exclusion criteria: has a history of stroke, chronic seizures, or major neurological disorder has received previous treatment with a direct-acting antiviral (DAA) has evidence of high grade bridging fibrosis from prior liver biopsy within 3 years of study entry has evidence or history of chronic hepatitis not caused by HCV infection including but not limited to non-HCV viral hepatitis, nonalcoholic steatohepatitis (NASH), drug-induced hepatitis, or autoimmune hepatitis has clinical or laboratory evidence of cirrhosis or other advanced liver disease has decompensated liver disease as indicated by a history of ascites, hepatic encephalopathy, or bleeding esophageal varices has been diagnosed with, or suspected of having, hepatocellular carcinoma (HCC) has clinically significant abnormality on an electrocardiogram (ECG) is co-infected with human immunodeficiency virus (HIV) is positive for Hepatitis B surface antigen (HBsAg) or other evidence of active Hepatitis B infection has a history of gastric bypass surgery, bowel resection or other disorder that may interfere with absorption has a history of clinically significant uncontrolled endocrine, gastrointestinal, cardiovascular, hematological, immunological, renal, respiratory, or genitourinary abnormalities or diseases has clinically significant neoplastic disease uses alcohol to excess, defined as greater than 3 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer [354 mL], wine [118 mL], or distilled spirits [29.5 mL]) per day is a current regular user (including use of any illicit drugs) or history of drug (including alcohol) abuse within the last 3 months has undergone surgery, donation of 1 unit of blood (approximately 500 mL) or participation in another investigational study within a period of 4 weeks prior to the screening visit has a history of multiple and/or severe allergies, or anaphylactic reaction or intolerability to prescription or nonprescription drugs or food is pregnant or lactating is expecting to donate eggs or sperm

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Grazoprevir 100 mg<br>Participants received GZR 100 mg once daily (q.d.) for 7 days. Liver FNA was performed on Day 7. | Drug: Grazoprevir<br>* GZR 100 mg tablet by mouth q.d. for 7 days.<br>* Other names: MK-5172;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimated Area Under the Liver Concentration-time Curve for 24 Hours Post-dose (AUC[H]0-24hr) of Grazoprevir | Each participant was assigned to undergo Fine Needle Aspiration (FNA) to obtain liver tissue at different time points. Specifically, one participant underwent FNA at 4 hr post-dose only, another participant underwent FNA at 8 hr post-dose only, and a third participant underwent FNA at 24 hr post-dose only. (The fourth participant underwent FNA at 72 hr post-dose and therefore was not included in the calculation of AUC0-24hr.) Therefore, in calculating AUC0-24hr, there were only 3 data points: 1 data point at 4 hr post-dose, 1 data point at 8 hr post-dose, and 1 data point at 24 hr post-dose. The model assumed that drug concentration was at steady-state, and that the concentration at 24 hr post-dose was equal to the concentration at 0 hr post-dose. | 4, 8, and 24 hours post-dose on Day 7 | 
| Hepatic Concentration of GZR (C[H]Xhr) | C(H)Xhr of GZR was expressed as liver concentration (μmol GZR/L liver) using the concentration of the extracted liver sample (mass of the liver biopsy/0.2 mL solvent), and assuming that liver has the specific gravity of water (1 g/mL). The arithmetic mean C(H)Xhr concentration is based on the means of 4 FNA passes per participant in all 4 participants. | 4, 8, 24, and 72 hours post-dose on Day 7 | 
| Apparent Terminal Hepatic Half-life (t[H]½ ) of GZR | t(H)1/2 is a measure of the time required for the maximum post-dose liver concentration of GZR to decrease by 50%. | 4, 8, 24, and 72 hours post-dose on Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma AUC[0-24 hr] of GZR | AUC0-24hr is a measure of the mean concentration of drug in plasma after dosing to 24 hours post-dose. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 and 72 hours post-dose on Day 7 | 
| Maximum Plasma Concentration (Cmax) of GZR | Cmax is a measure of the maximum plasma concentration post-dose. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 and 72 hours post-dose on Day 7 | 
| Lowest Plasma Concentration (Ctrough) of GZR | Ctrough is a measure of drug concentration 24 hours post-dose. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 and 72 hours post-dose on Day 7 | 
| Time to Maximum Plasma Concentration (Tmax) of GZR | Tmax is a measure of time to reach maximum post-dose plasma drug concentration. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 and 72 hours post-dose on Day 7 | 
| Plasma t½ of GZR | t1/2 is a measure of time for the maximum plasma concentration of GZR to decrease by 50%. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 and 72 hours post-dose on Day 7 |