Hwa-Ping Feng

Pharmacokinetic interaction between the hepatitis C virus protease inhibitor boceprevir and cyclosporine and tacrolimus in healthy volunteers

The hepatitis C virus protease inhibitor boceprevir is a strong inhibitor of cytochrome P450 3A4 and 3A5 (CYP3A4/5). Cyclosporine and tacrolimus are calcineurin inhibitor immunosuppressants used to prevent organ rejection after liver transplantation; both are substrates of CYP3A4. This two‐part pharmacokinetic interaction study evaluated boceprevir with cyclosporine (part 1) and tacrolimus (part 2). In part 1, 10 subjects received single‐dose cyclosporine (100 mg) on day 1, single‐dose boceprevir (800 mg) on day 3, and concomitant cyclosporine/boceprevir on day 4. After washout, subjects received boceprevir (800 mg three times a day) for 7 days plus single‐dose cyclosporine (100 mg) on day 6. In part 2A, 12 subjects received single‐dose tacrolimus (0.5 mg). After washout, they received boceprevir (800 mg three times a day) for 11 days plus single‐dose tacrolimus (0.5 mg) on day 6. In part 2B, 10 subjects received single‐dose boceprevir (800 mg) and 24 hours later received boceprevir (800 mg) plus tacrolimus (0.5 mg). Coadministration of boceprevir with cyclosporine/tacrolimus was well tolerated. Concomitant boceprevir increased the area under the concentration‐time curve from time 0 to infinity after single dosing (AUCinf) and maximum observed plasma (or blood) concentration (Cmax) of cyclosporine with geometric mean ratios (GMRs) (90% confidence interval [CI]) of 2.7 (2.4‐3.1) and 2.0 (1.7‐2.4), respectively. Concomitant boceprevir increased the AUCinf and Cmax of tacrolimus with GMRs (90% CI) of 17 (14‐21) and 9.9 (8.0‐12), respectively. Neither cyclosporine nor tacrolimus coadministration had a meaningful effect on boceprevir pharmacokinetics. Conclusion: Dose adjustments of cyclosporine should be anticipated when administered with boceprevir, guided by close monitoring of cyclosporine blood concentrations and frequent assessments of renal function and cyclosporine‐related side effects. Administration of boceprevir plus tacrolimus requires significant dose reduction and prolongation of the dosing interval for tacrolimus, with close monitoring of tacrolimus blood concentrations and frequent assessments of renal function and tacrolimus‐related side effects. (HEPATOLOGY 2012;56:1622–1630)

Pharmacokinetic Interactions Between the Hepatitis C Virus Protease Inhibitor Boceprevir and Ritonavir-Boosted HIV-1 Protease Inhibitors Atazanavir, Darunavir, and Lopinavir

BACKGROUND Boceprevir represents a new treatment option for hepatitis C (HCV)-infected patients, including those with HCV/human immunodeficiency virus coinfection; however, little is known about pharmacokinetic interactions between boceprevir and antiretroviral drugs. METHODS A randomized, open-label study to assess the pharmacokinetic interactions between boceprevir and ritonavir-boosted protease inhibitors (PI/r) was conducted in 39 healthy adults. Subjects received boceprevir (800 mg, 3 times daily) for 6 days and then received PI/r as follows: atazanavir (ATV) 300 mg once daily, lopinavir (LPV) 400 mg twice daily, or darunavir (DRV) 600 mg twice daily, each with ritonavir (RTV) 100 mg on days 10-31, plus concomitant boceprevir on days 25-31. RESULTS Boceprevir decreased the exposure of all PI/r, with area under the concentration-time curve [AUC] from time 0 to the time of the last measurable sample geometric mean ratios of 0.65 (90% confidence interval [CI], .55-.78) for ATV/r; 0.66 (90% CI, .60-.72) for LPV/r, and 0.56 (90% CI, .51-.61) for DRV/r. Coadministration with boceprevir decreased RTV AUC during a dosing interval τ (AUC(τ)) by 22%-36%. ATV/r did not significantly affect boceprevir exposure, but boceprevir AUC(τ) was reduced by 45% and 32% when coadministered with LPV/r and DRV/r, respectively. Overall, treatments were well tolerated with no unexpected adverse events. CONCLUSIONS Concomitant administration of boceprevir with PI/r resulted in reduced exposures of PI and boceprevir. These drug-drug interactions may reduce the effectiveness of PI/r and/or boceprevir when coadministered.

Pharmacokinetic Evaluation of the Interaction between Hepatitis C Virus Protease Inhibitor Boceprevir and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Atorvastatin and Pravastatin

ABSTRACT Boceprevir is a potent orally administered inhibitor of hepatitis C virus and a strong, reversible inhibitor of CYP3A4, the primary metabolic pathway for many 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Thus, the aim of the present study was to investigate drug-drug interactions between atorvastatin or pravastatin and boceprevir. We conducted a single-center, open-label, fixed-sequence, one-way-crossover study with 20 healthy adult volunteers. Subjects received single-dose atorvastatin (40 mg) or pravastatin (40 mg) on day 1, followed by boceprevir (800 mg three times daily) for 7 to 10 days. Repeat single doses of atorvastatin or pravastatin were administered in the presence of steady-state boceprevir. Atorvastatin exposure increased in the presence of boceprevir, with atorvastatin area under the concentration-time curve from time zero to infinity after single dosing (AUCinf) increasing 2.3-fold (90% confidence interval [CI], 1.85, 2.90) and maximum observed concentration in plasma (Cmax) 2.7-fold (90% CI, 1.81, 3.90). Pravastatin exposure was slightly increased in the presence of boceprevir, with pravastatin AUCinf increasing 1.63-fold (90% CI, 1.03, 2.58) and Cmax 1.49-fold (90% CI, 1.03, 2.14). Boceprevir exposure was generally unchanged when the drug was coadministered with atorvastatin or pravastatin. All adverse events were mild and consistent with the known safety profile of boceprevir. The observed 130% increase in AUC of atorvastatin supports the use of the lowest possible effective dose of atorvastatin when coadministered with boceprevir, without exceeding a maximum daily dose of 40 mg. The observed 60% increase in pravastatin AUC with boceprevir coadministration supports the initiation of pravastatin treatment at the recommended dose when coadministered with boceprevir, with close clinical monitoring.

Clinical pharmacology profile of boceprevir, a hepatitis C virus NS3 protease inhibitor: focus on drug-drug interactions.

Boceprevir is a potent, orally administered ketoamide inhibitor that targets the active site of the hepatitis C virus (HCV) non-structural (NS) 3 protease. The addition of boceprevir to peginterferon plus ribavirin resulted in higher rates of sustained virologic response (SVR) than for peginterferon plus ribavirin alone in phase III studies in both previously treated and untreated patients with HCV infection. Because boceprevir is metabolized by metabolic routes common to many other drugs, and is an inhibitor of cytochrome P450 (CYP) 3A4/5, there is a high potential for drug–drug interactions when boceprevir is administered with other therapies, particularly when treating patients with chronic HCV infection who are often receiving other medications concomitantly. Boceprevir is no longer widely used in the US or EU due to the introduction of second-generation treatments for HCV infection. However, in many other geographic regions, first-generation protease inhibitors such as boceprevir continue to form an important treatment option for patients with HCV infection. This review summarizes the interactions between boceprevir and other therapeutic agents commonly used in this patient population, indicating dose adjustment requirements where needed. Most drug interactions do not affect boceprevir plasma concentrations to a clinically meaningful extent, and thus efficacy is likely to be maintained when boceprevir is coadministered with the majority of other therapeutics. Overall, the drug–drug interaction profile of boceprevir suggests that this agent is suitable for use in a wide range of HCV-infected patients receiving concomitant therapies.

463 PHARMACOKINETIC INTERACTIONS BETWEEN THE HCV PROTEASE INHIBITOR BOCEPREVIR AND SIROLIMUS IN HEALTHY SUBJECTS

Background and Aims: Boceprevir is a potent, orally administered, ketoamide inhibitor of the hepatitis C virus (HCV) NS3 protease. HCV-related end-stage liver disease and hepatocellular carcinoma are frequent causes of liver transplantation. Sirolimus is a macrolide immunosuppressant frequently used for the prophylaxis of transplant rejection. This study was conducted to evaluate the pharmacokinetic interaction of boceprevir and sirolimus in healthy volunteers. Methods: In this open-label, 3-period, fixed-sequence trial, 12 subjects received single-dose sirolimus (2mg) in period 1 and boceprevir (800mg TID for 6 days) in period 2 with an intervening washout of 14 days. Period 3 immediately followed period 2 with no intervening washout: subjects received sirolimus (2mg SD) plus boceprevir (800mg TID) on day 1 and boceprevir (800mg TID) thereafter for 9 days. Blood samples were collected for the pharmacokinetic assessment of sirolimus and boceprevir. Safety assessments included electrocardiograms, vital signs, clinical laboratory tests, physical examination, and adverse event monitoring. Results: Twelve healthy volunteers were enrolled and 11 completed the trial. Coadministration of boceprevir and sirolimus was well tolerated. Boceprevir co-administration increased the geometric mean AUC0–∞ and Cmax of sirolimus by 8.1-fold and 4.8-fold, respectively, with the corresponding 90% CIs of (7.08, 9.32) for AUC0–∞ and (3.99, 5.88) for Cmax. The elimination half-life of sirolimus increased from 82.5 h to 98.3 h, and the apparent clearance decreased from 9.62 L/min to 1.18 L/min, respectively, with boceprevir coadministration. Sirolimus co-administration did not affect the pharmacokinetics of boceprevir (AUC0–8h and Cmax GMR [90%CI] of 1.0 [0.89, 1.01] and 0.9 [0.82, 1.07], respectively). Conclusions: Concomitant administration of boceprevir and sirolimus resulted in increased steady-state exposures of sirolimus in healthy subjects. The magnitude of the potential interaction between sirolimus and boceprevir in organ transplant patients is not known, but could potentially be higher and more variable than that seen in healthy volunteers. Dose adjustment of sirolimus and/or prolongation of the dosing interval should be anticipated when administered with boceprevir, and should be guided by close monitoring of sirolimus blood concentrations, and frequent assessment of renal function and sirolimus-related side effects.

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.

Concomitant proton pump inhibitor use does not reduce the efficacy of elbasvir/grazoprevir: A pooled analysis of 1,322 patients with hepatitis C infection

Concomitant proton pump inhibitor (PPI) use reduces plasma concentrations of certain nonstructural protein 5A inhibitors, which are key components of modern hepatitis C infection (HCV) treatments. These reduced concentrations may decrease efficacy, leading to challenging treatment failures due to the development of resistance‐associated substitutions. This post‐hoc analysis assessed 12‐week sustained viral response (SVR12) and pharmacokinetics of fixed‐dose combination elbasvir/grazoprevir (EBR/GZR) in patients with HCV infection and self‐reported PPI use. Data were derived from six phase 3 EBR/GZR trials with treatment‐naive or treatment‐experienced genotype 1‐ or 4‐infected patients, with or without compensated cirrhosis. Baseline PPI use was defined as ≥7 consecutive days of use between study days –7 and 7. Bivariate analyses assessed PPI use and factors associated with SVR12 with sex, age (continuous and dichotomous), cirrhosis status, prior treatment status, baseline HCV RNA (continuous and dichotomous), HCV genotype, and baseline resistance‐associated substitutions as variables in the models. Overall, 12% (162/1,322) of EBR/GZR‐treated patients reported baseline PPI use. Of those, 96% achieved SVR12. In patients without PPI use, 97% achieved SVR12. PPI use was not a predictive factor in achieving SVR12 based on a univariate analysis (P = 0.188). In the bivariate models, none of the interaction terms involving PPI use were statistically significant. There was no significant effect of PPI usage, regardless of adjustment for considered factors. The estimated area under the curve and maximum concentration values for EBR were comparable among patients with and without reported PPI use. Conclusion: These results demonstrate that PPI use with EBR/GZR had no clinically significant effect on SVR12 rates in genotype 1/4‐infected patients with or without compensated cirrhosis. (clinicaltrials.gov identifiers: NCT02092350, NCT02105467, NCT02105662, NCT02105688, NCT02105701, NCT02358044) (Hepatology Communications 2017;1:757–764)