Wendy W. Yeh

Susceptibilities of Genotype 1a, 1b, and 3 Hepatitis C Virus Variants to the NS5A Inhibitor Elbasvir

ABSTRACT Elbasvir is an investigational NS5A inhibitor with in vitro activity against multiple HCV genotypes. Antiviral activity of elbasvir was measured in replicons derived from wild-type or resistant variants of genotypes 1a, 1b, and 3. The barrier to resistance was assessed by the number of resistant colonies selected by exposure to various elbasvir concentrations. In a phase 1b dose-escalating study, virologic responses were determined in 48 noncirrhotic adult men with chronic genotype 1 or 3 infections randomized to placebo or elbasvir from 5 to 50 mg (genotype 1) or 10 to 100 mg (genotype 3) once daily for 5 days. The NS5A gene was sequenced from plasma specimens obtained before, during, and after treatment. Elbasvir suppressed the emergence of resistance-associated variants (RAVs) in vitro in a dose-dependent manner. Variants selected by exposure to high elbasvir concentrations typically encoded multiple amino acid substitutions (most commonly involving loci 30, 31, and 93), conferring high-level elbasvir resistance. In the monotherapy study, patients with genotype 1b had greater reductions in HCV RNA levels than patients with genotype 1a at all elbasvir doses; responses in patients with genotype 3 were generally less pronounced than for genotype 1, particularly at lower elbasvir doses. M28T, Q30R, L31V, and Y93H in genotype 1a, L31V and Y93H in genotype 1b, and A30K, L31F, and Y93H in genotype 3 were the predominant RAVs selected by elbasvir monotherapy. Virologic findings in patients were consistent with the preclinical observations. NS5A-RAVs emerged most often at amino acid positions 28, 30, 31, and 93 in both the laboratory and clinical trial. (The MK-8742 P002 trial has been registered at ClinicalTrials.gov under identifier NCT01532973.)

No Pharmacokinetic Interaction Between the Hepatitis C Virus Inhibitors Elbasvir/Grazoprevir and Famotidine or Pantoprazole

Use of agents to suppress gastric acid secretion is common among patients with hepatitis C virus (HCV) infection. The aims of this open‐label, three‐period, fixed‐sequence study were to evaluate the effect of famotidine and pantoprazole on the pharmacokinetics and safety of elbasvir/grazoprevir fixed‐dose combination (FDC) in 16 healthy subjects. Elbasvir and grazoprevir each exhibited similar pharmacokinetics following single‐dose administration of elbasvir/grazoprevir with or without famotidine or pantoprazole. Geometric mean ratios (GMRs) of grazoprevir AUC(0,∞), Cmax, and C24 (elbasvir/grazoprevir + famotidine or elbasvir/grazoprevir + pantoprazole vs. elbasvir/grazoprevir) ranged from 0.89–1.17. Similarly, GMRs of elbasvir AUC(0,∞), Cmax, and C24 (elbasvir/grazoprevir + famotidine or elbasvir/grazoprevir + pantoprazole vs. elbasvir/grazoprevir) ranged from 1.02–1.11. These results indicate that gastric acid‐reducing agents do not modify the pharmacokinetics of elbasvir or grazoprevir in a clinically relevant manner and may be coadministered with elbasvir/grazoprevir in HCV‐infected patients without restriction.

No clinically meaningful pharmacokinetic interaction between the hepatitis C virus inhibitors elbasvir and grazoprevir and the oral contraceptives ethinyl estradiol and levonorgestrel

PurposeOral contraceptive pills (OCPs) are an important element of hepatitis C virus (HCV) treatment in women of childbearing potential. These studies evaluated the safety and pharmacokinetic interactions between elbasvir (EBR) and grazoprevir (GZR) and ethinyl estradiol/levonorgestrel (EE/LNG).MethodsBoth studies were open-label, single-site, two-period, fixed-sequence, one-way interaction studies. In period 1, subjects received one tablet of EE/LNG (0.03xa0mg/0.15xa0mg). In period 2, subjects received EBR (50xa0mg once daily) for 13xa0days or GZR (200xa0mg once daily) for 10xa0days, with one tablet of EE/LNG on day 7 (GZR group) or 10 (EBR group). Each study enrolled 20 healthy, nonsmoking adult females.ResultsThere was no clinically meaningful effect of multiple doses of EBR or GZR on the pharmacokinetics of EE or LNG. Geometric mean ratios (GMRs) for AUC0–∞ and Cmax in the presence and absence of EBR were 1.01 and 1.10 for EE and 1.14 and 1.02 for LNG, with 90% confidence intervals (CIs) that were contained in the interval [0.80, 1.25]. Similarly, the AUC0–∞ and Cmax GMRs in the presence and absence of GZR were 1.10 and 1.05 for EE and 1.23 and 0.93 for LNG, respectively. The 90% CIs for EE AUC0–∞ and for EE and LNG Cmax were contained in the interval [0.80, 1.25]; however, the 90% CI for the LNG AUC0–∞ [1.15, 1.32] slightly exceeded the upper bound.ConclusionsThese results suggest that EBR/GZR can be co-administered to female patients with HCV of childbearing potential who are on OCPs to prevent pregnancy.

Effect of hepatic impairment on the pharmacokinetics of grazoprevir, a hepatitis C virus protease inhibitor

ABSTRACT Grazoprevir (GZR) plus elbasvir is an approved treatment for chronic infection with hepatitis C virus (HCV) genotype 1 or 4. HCV infection complications include liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The objective of this study was to evaluate the pharmacokinetics and safety of multiple-dose GZR (200, 100, or 50 mg) in non-HCV participants with mild, moderate, or severe hepatic impairment (HI), respectively, and in healthy matched controls (protocol MK-5172_p013; Merck & Co., Inc., Kenilworth, NJ). Participants with mild, moderate, or severe HI and controls (aged 18 to 65 years) matched for race, age, sex, and body mass index were enrolled in a 3-part, open-label, sequential-panel pharmacokinetic study. Participants received oral doses of GZR 200 mg (two 100-mg tablets), 100 mg (one 100-mg tablet), or 50 mg (two 25-mg tablets) once daily for 10 days. A total of 50 participants were enrolled: 8 with mild HI, 9 with moderate HI, 8 with severe HI, and a corresponding number of healthy matched controls for each hepatic cohort. Participants with HI demonstrated higher GZR exposure than healthy matched controls and showed an increase in exposure with increasing HI severity. The steady-state GZR AUC0–24 (area under the concentration-time curve from 0 to 24 h) for participants with mild, moderate, or severe HI was ≈2-, ≈5-, or ≈12-fold higher, respectively, than that for healthy matched controls. GZR was generally well tolerated in participants with HI. No dose adjustment is required for GZR in people with HCV with mild HI. GZR is contraindicated for those with moderate or severe HI (Child-Pugh class B or C), since they may have significantly increased GZR exposures that may lead to an increased risk of transaminase elevation.

Pharmacokinetics, Safety, and Tolerability of Single-Dose Elbasvir in Participants with Hepatic Impairment

BackgroundThe combination of elbasvir and grazoprevir is approved for the treatment of hepatitis C virus genotype 1 or 4 infection.ObjectiveTo evaluate the pharmacokinetics and safety of single-dose elbasvir 50xa0mg in participants with hepatic impairment.MethodsParticipants with mild, moderate, or severe hepatic impairment and age-, sex-, and weight-matched healthy controls were enrolled in a 3-part, open-label, sequential-panel, single-dose pharmacokinetic study. Blood samples were collected to assess pharmacokinetics. Safety and tolerability were assessed throughout the study.ResultsThirty-four participants were enrolled: eight with mild hepatic impairment, 11 with moderate hepatic impairment, seven with severe hepatic impairment, and eight healthy matched controls. Participants with mild, moderate, and severe hepatic impairment demonstrated a numeric, but not statistically significant, decrease in elbasvir exposure compared with controls, with a mean 39, 28, and 12% decrease in area under the concentration–time curve from time 0 extrapolated to infinity, as well as a 42, 31, and 42% decrease in maximum plasma concentration (Cmax), respectively. The observed median time to Cmax was similar in participants with hepatic impairment and controls. Single-dose administration of elbasvir was well tolerated.ConclusionsThe pharmacokinetics of elbasvir after a single, oral 50-mg dose were not clinically meaningfully altered in non–HCV-infected participants with mild, moderate, or severe hepatic dysfunction. However, since elbasvir is currently available only as part of a fixed-dose combination with grazoprevir, the fixed-dose combination should not be administered to patients with moderate or severe hepatic impairment, due to the significantly increased plasma grazoprevir exposures in those populations.

P0910 : No evidence of pharmacokinetic drug–drug interaction in healthy subjects between coadministered grazoprevir (MK-5172)/elbasvir (MK-8742) and sofosbuvir

Background and aims: Grazoprevir (MK-5172), a potent inhibitor of the hepatitis C virus (HCV) NS3/4A protease, and elbasvir (MK-8742), a potent inhibitor of the HCV NS5A replication complex, are being developed evaluated the effect of grazoprevir and elbasvir on the pharmacokinetics of sofosbuvir (SOF), an HCV NS5B inhibitor, when coadministered in healthy subjects. Methods: grazoprevir and elbasvir on the pharmacokinetics of a single oral dose of SOF. Sixteen (16) healthy adult male and female subjects were enrolled. In Period 1, subjects received a single oral 400-mg dose of SOF. Following an 8-day washout period, multiple oral doses of 200 mg grazoprevir and 50 mg elbasvir were coadministered QD from Days 1 to 15, inclusive, in Period 2. On Day 11, a single oral dose of SOF was coadministered with the dose of grazoprevir and elbasvir. Plasma pharmacokinetic parameters of SOF and its principal nucleoside metabolite (GS-331007) were measured in Period 1 and following the dose on Day 11 in Period 2. Results: (90% CIs)] for plasma SOF AUC0-∞ and Cmax were 2.43 [2.12, 2.79] and 2.27 [1.72, 2.99], respectively. These changes in SOF exposure are not considered to be clinically meaningful based on the safety margins of SOF. The GMRs [90% CIs] for plasma GS-331007 AUC0-∞ and Cmax for the same comparison were 1.13 [1.05, 1.21] and 0.87 [0.78, 0.96], respectively. These changes in GS-331007 exposure are not considered to be clinically meaningful. Coadministration of SOF, grazoprevir, and elbasvir was generally well tolerated. Conclusions: Multiple-dose administration of 200 mg grazoprevir and 50 mg elbasvir daily with a single dose of SOF was generally well tolerated by healthy subjects in this study. Coadministration of elbasvir and grazoprevir with SOF had no clinically meaningful effect on the pharmacokinetics of SOF and its metabolite GS-331007. Taken together with the lack of potential for SOF to perpetrate a drug-drug interaction on grazoprevir or elbasvir, these results suggest that SOF, grazoprevir, and elbasvir may be coadministered without dose adjustment.

Pharmacokinetic Interactions Between Elbasvir/Grazoprevir and Immunosuppressant Drugs in Healthy Volunteers

Elbasvir (EBR)/grazoprevir (GZR) may be coadministered with immunosuppressant drugs in posttransplant people who are infected with hepatitis C virus. The aim of the present study was to assess the safety and pharmacokinetic interactions between EBR and GZR and single doses of cyclosporine, tacrolimus, mycophenolate mofetil (MMF), and prednisone. This was a 4‐part, open‐label study in 58 healthy volunteers. Participants received single doses of cyclosporine 400 mg, tacrolimus 2 mg, MMF 1 g, or prednisone 40 mg alone or in the presence of once‐daily EBR 50 mg/GZR 200 mg. Multiple oral doses of EBR + GZR had no significant effect on cyclosporine. However, in the presence of cyclosporine, the 24‐hour area under the concentration‐time curve of GZR was increased by approximately 15‐fold (geometric mean ratio [90%CI] 15.21 [12.83; 18.04]); the concentration of EBR was increased approximately 2‐fold in the presence of cyclosporine. Coadministration of EBR/GZR and tacrolimus did not affect the pharmacokinetics of EBR or GZR, but resulted in an increase in tacrolimus AUC (geometric mean ratio [90%CI] 1.43 [1.24; 1.64]). There were no clinically relevant interactions between EBR/GZR and either MMF or prednisone. Data from the present study indicate that EBR/GZR may be coadministered in people receiving tacrolimus, MMF, and prednisolone. EBR/GZR is contraindicated in people receiving cyclosporine because the significantly higher concentrations of GZR may increase the risk of transaminase elevations.

No Pharmacokinetic Interactions Between Elbasvir or Grazoprevir and Methadone in Participants Receiving Maintenance Opioid Agonist Therapy

We conducted two phase I trials to evaluate the pharmacokinetic interactions between elbasvir (EBR), grazoprevir (GZR), and methadone (MK‐8742‐P010 and MK‐5172‐P030) in non‐hepatitis C virus (HCV)‐infected participants on methadone maintenance therapy. Coadministration of EBR or GZR with methadone had no clinically meaningful effect on EBR, GZR, or methadone pharmacokinetics. The geometric mean ratios (GMRs) for R‐ and S‐methadone AUC0‐24 were 1.03 (90% confidence interval (CI), 0.92–1.15) and 1.09 (90% CI, 0.94–1.26) in the presence/absence of EBR; and 1.09 (90% CI, 1.02–1.17) and 1.23 (90% CI, 1.12–1.35) in the presence/absence of GZR. The GMRs for EBR and GZR AUC0‐24 in participants receiving methadone relative to a healthy historical cohort not receiving methadone were 1.20 (90% CI, 0.94–1.53) and 1.03 (90% CI, 0.76–1.41), respectively. These results indicate that no dose adjustment is required for individuals with HCV infection receiving stable methadone therapy and the EBR/GZR fixed‐dose regimen.

No Pharmacokinetic Interactions Between Elbasvir or Grazoprevir and Buprenorphine/Naloxone in Healthy Participants and Participants Receiving Stable Opioid Agonist Therapy

The aims of these phase I trials were to evaluate the pharmacokinetic interaction between elbasvir (EBR) or grazoprevir (GZR) and buprenorphine/naloxone (BUP/NAL). Trial 1 was a single‐dose trial in healthy participants. Trial 2 was a multiple‐dose trial in participants on BUP/NAL maintenance therapy. Coadministration of EBR or GZR with BUP/NAL had minimal effect on the pharmacokinetics of BUP/NAL, EBR, and GZR. The geometric mean ratios (GMRs (90% CI)) for BUP, norbuprenorphine, and NAL AUC0‐∞ were 0.98 (0.89–1.08), 0.97 (0.86–1.09), and 0.88 (0.78–1.00) in the presence/absence of EBR; 0.98 (0.81–1.19), 1.13 (0.97–1.32), and 1.10 (0.82–1.47) in the presence/absence of GZR. The GMRs (90% CI) for EBR and GZR AUC0‐∞ in the absence/presence of BUP/NAL were 1.22 (0.98–1.52) and 0.86 (0.63–1.18). In conclusion, no dose adjustment for BUP/NAL, EBR, or GZR is required for patients with HCV infection receiving EBR/GZR and BUP/NAL maintenance therapy.

Antiviral Activity, Safety, and Tolerability of Multiple Ascending Doses of Elbasvir or Grazoprevir in Participants Infected With Hepatitis C Virus Genotype-1 or -3

PURPOSEnElbasvir (MK-8742) and grazoprevir (MK-5172; Merck & Co, Inc, Kenilworth, New Jersey) are hepatitis C virus (HCV)-specific inhibitors of the nonstructural protein 5A phosphoprotein and the nonstructural protein 3/4A protease, respectively. The aims of these studies were to evaluate the antiviral activity and safety of different doses of elbasvir or grazoprevir each administered as monotherapy to participants infected with either HCV genotype (GT) 1 or GT3.nnnMETHODSnThese 2 double-blind, randomized, placebo-controlled, sequential-panel, multiple ascending dose studies were conducted to assess the safety and pharmacodynamics of 5 days of once-daily elbasvir or 7 days of once-daily grazoprevir in adult male participants chronically infected with either HCV GT1 or GT3.nnnFINDINGSnOral administration of elbasvir or grazoprevir once daily exhibited potent antiviral activity in participants with chronic GT1 or GT3 HCV infections. HCV RNA levels declined rapidly (within 1 day for elbasvir and 2 days for grazoprevir). At 50 mg of elbasvir once daily, the mean maximum reductions in HCV RNA from baseline were 5.21, 4.17, and 3.12 log10 IU/mL for GT1b-, GT1a-, and GT3-infected participants, respectively. At 100 mg of grazoprevir once daily, the mean maximum reductions in HCV RNA from baseline were 4.74 and 2.64 log10 IU/mL for GT1- and GT3-infected participants.nnnIMPLICATIONSnThe results in the elbasvir monotherapy study showed that 10 to 50 mg of elbasvir was associated with a rapid decline in HCV viral load; the results in the grazoprevir monotherapy study suggest that doses of 50 mg of grazoprevir and higher are on the maximum response plateau of the dose-response curve for GT1-infected participants. The results of these proof-of-concept studies provided preliminary data for the selection of the dosages of elbasvir and grazoprevir to test in Phase II and III clinical studies. ClinicalTrials.gov identifiers: NCT00998985 (Protocol 5172-004) and NCT01532973 (Protocol 8742-002).