Hepatitis C
Conditions
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).
Interventions
DRUGGrazoprevir
GZR 100 mg tablet by mouth q.d. for 7 days.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Estimated Area Under the Liver Concentration-time Curve for 24 Hours Post-dose (AUC[H]0-24hr) of Grazoprevir | 4, 8, and 24 hours post-dose on Day 7 | 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. |
| Hepatic Concentration of GZR (C[H]Xhr) | 4, 8, 24, and 72 hours post-dose on Day 7 | 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. |
| Apparent Terminal Hepatic Half-life (t[H]½ ) of GZR | 4, 8, 24, and 72 hours post-dose on Day 7 | t(H)1/2 is a measure of the time required for the maximum post-dose liver concentration of GZR to decrease by 50%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximum Plasma Concentration (Tmax) of GZR | 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 | Tmax is a measure of time to reach maximum post-dose plasma drug concentration. |
| Plasma AUC[0-24 hr] of GZR | 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 | AUC0-24hr is a measure of the mean concentration of drug in plasma after dosing to 24 hours post-dose. |
| Plasma t½ of GZR | 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 | t1/2 is a measure of time for the maximum plasma concentration of GZR to decrease by 50%. |
| Maximum Plasma Concentration (Cmax) of GZR | 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 | Cmax is a measure of the maximum plasma concentration post-dose. |
| Lowest Plasma Concentration (Ctrough) of GZR | 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 | Ctrough is a measure of drug concentration 24 hours post-dose. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Grazoprevir 100 mg Participants received GZR 100 mg q.d. for 7 days. Liver FNA was performed on Day 7. | 4 |
| Total | 4 |
Baseline characteristics
| Characteristic | Grazoprevir 100 mg |
|---|---|
| Age, Continuous | 42.5 Years STANDARD_DEVIATION 12.9 |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 1 / 4 |
| serious Total, serious adverse events | 1 / 4 |
Outcome results
Primary
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%.
Time frame: 4, 8, 24, and 72 hours post-dose on Day 7
Population: Apparent t(h)1/2 could not be estimated due to insufficient data in the terminal phase.
Primary
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.
Time frame: 4, 8, and 24 hours post-dose on Day 7
Population: The per protocol population (PPP) includes all participants (4, 8, and 24 hr time points) who complied with the protocol sufficiently to ensure that the data were likely to exhibit the effects of treatment. As each data point was obtained from unique participants, there is no measure of variability.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grazoprevir 100 mg | Estimated Area Under the Liver Concentration-time Curve for 24 Hours Post-dose (AUC[H]0-24hr) of Grazoprevir | 19800 µM*hr |
Primary
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.
Time frame: 4, 8, 24, and 72 hours post-dose on Day 7
Population: The PPP includes all participants who complied with the protocol sufficiently to ensure that the data were likely to exhibit the effects of treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Grazoprevir 100 mg | Hepatic Concentration of GZR (C[H]Xhr) | Hepatic concentration at 4 hours (C[H]4hr) | 390 µM | Standard Deviation 186 |
| Grazoprevir 100 mg | Hepatic Concentration of GZR (C[H]Xhr) | Hepatic concentration at 8 hours (C[H]8hr) | 1340 µM | Standard Deviation 1335 |
| Grazoprevir 100 mg | Hepatic Concentration of GZR (C[H]Xhr) | Hepatic concentration at 24 hours (C[H]24hr) | 575 µM | Standard Deviation 505 |
| Grazoprevir 100 mg | Hepatic Concentration of GZR (C[H]Xhr) | Hepatic concentration at 72 hours (C[H]72hr) | 434 µM | Standard Deviation 108 |
Secondary
Lowest Plasma Concentration (Ctrough) of GZR
Ctrough is a measure of drug concentration 24 hours post-dose.
Time frame: 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
Population: Plasma PK data were not collected due to liver PK results being deemed physiologically impossible.
Secondary
Maximum Plasma Concentration (Cmax) of GZR
Cmax is a measure of the maximum plasma concentration post-dose.
Time frame: 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
Population: Plasma PK data were not collected due to liver PK results being deemed physiologically impossible.
Secondary
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.
Time frame: 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
Population: Plasma PK data were not collected due to liver PK results being deemed physiologically impossible.
Secondary
Plasma t½ of GZR
t1/2 is a measure of time for the maximum plasma concentration of GZR to decrease by 50%.
Time frame: 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
Population: Plasma PK data were not collected due to liver PK results being deemed physiologically impossible.
Secondary
Time to Maximum Plasma Concentration (Tmax) of GZR
Tmax is a measure of time to reach maximum post-dose plasma drug concentration.
Time frame: 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
Population: Plasma PK data were not collected due to liver PK results being deemed physiologically impossible.