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Meeting Report - 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy (June 22-23, 2011, Boston, MA)
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Jennifer Kiser, PharmD
University of Colorado Denver
The 6th International Workshop on Clinical Pharmacology of Hepatitis Therapy was held in Boston, MA June 22-23, 2011. The Workshop provides a forum for individuals from academia, industry, and regulatory agencies to present data, discuss topics, and identify research needs related to the clinical pharmacology of hepatitis therapy. At this year's meeting, there was naturally a lot of excitement around the approval of the Hepatitis C virus (HCV) protease inhibitors (PI), boceprevir and telaprevir. Twice as many abstracts were presented at this year's Workshop compared with 2010 and attendance has increased. Workshop attendees have a strong desire to ensure we use our current and future HCV agents in the most informed manner possible based on a significant understanding of their clinical pharmacology. This report does not cover all lectures, oral abstracts and posters presented at the Workshop. For more information or to view presentations from the meeting, visit www.virology-education.com.
FDA and EMA Perspectives
Representatives from both the Food and Drug Administration (FDA) and European Medicines Agency (EMA) gave presentations at this meeting on the regulatory requirements for early clinical testing of novel HCV antiviral drugs. Sarah Robertson (FDA) and Filip Josephson (Swedish Medical Products Agency) stated that assessments of the dossiers' for boceprevir and telaprevir have led to modifications to both the FDA and EMA draft guidances on the development of direct-acting antiviral agents for the treatment of HCV. Furthermore, the change in the standard of care to triple therapy with peginterferon, ribavirin, plus a protease inhibitor has important implications for clinical trial designs (i.e. study control arms). Both spoke to considerations for trials of antiviral combinations (including in special patient populations); the data needed before the start of such trials, and possible study designs. Companies are encouraged to develop a plan for drug interaction studies before the start of Phase 2 trials.
Special Populations
Following telaprevir and boceprevir approval, the next major challenge in the treatment of HCV is how to manage patients with HIV coinfection, post-transplantation, advanced liver disease (i.e., pre-transplant), and renal impairment. Ray Chung (Massachusetts General Hospital) spoke to treatment considerations and I reviewed drug interaction studies in these special patient populations. Important gaps in knowledge and research needs in these populations relate to questions of efficacy and tolerability, the development of drug resistance, and of course, pharmacology. Specifically, in terms of pharmacology, there is a need to characterize drug pharmacokinetics and appropriate dosing and the identification and management of drug interactions in these important patient groups.
Protease Inhibitors
Vertex has developed an impressive portfolio of studies to characterize the pharmacology and interaction potential of telaprevir. Some drug interactions observed with telaprevir are unexpected or perplexing, but it appears they may occur at the level of bioavailability or due to protein-binding displacement. The results of several healthy volunteer drug-drug interaction studies and data on protein binding and pharmacokinetics in hepatic impairment were reported at this meeting.
· Hepatic impairment: Relative to participants with no hepatic impairment, telaprevir area under the curve (AUC) and maximum concentration (Cmax) were reduced 46% and 49%, respectively in those with moderate hepatic impairment following multiple doses of telaprevir. This is counterintuitive, but also observed with ritonavir and attributed to reduced absorption (Peng J, et al. 4th International Workshop on Clinical Pharmacology of HIV Therapy, abstract 3.7).
· Protein Binding: Some drug interactions with telaprevir may be mediated by protein binding displacement. However, measuring unbound telaprevir levels is not easily done retrospectively in clinical samples as the formic acid solution added to plasma to prevent telaprevir epimerization and allow accurate quantification of telaprevir and its R-diastereomer denatures plasma proteins. In vitro, 14C-telaprevir is 59-76% bound to plasma proteins (alpha-1 acid glycoprotein and albumin). Protein binding of 14C-telaprevir decreased with increasing concentrations of 14C-telaprevir or with decreased concentrations of alpha-1 acid glycoprotein or albumin. Protein binding interactions with warfarin were investigated in vitro. Warfarin binding was unaffected by telaprevir, but 14C-telaprevir free fraction was increased approximately 30% by warfarin. This indicates that drugs like warfarin with high affinity binding to alpha-1 acid glycoprotein or albumin may displace telaprevir from binding sites, leading to more unbound drug which is then available for metabolism and elimination resulting in lower apparent total telaprevir concentrations.
· Drug Interactions:
o Digoxin is a substrate of the drug transporter P-glycoprotein. Telaprevir increased digoxin Cmax and AUC by 1.5-fold and 1.85-fold, respectively, so lower doses of digoxin may be needed in patients on telaprevir and digoxin concentrations should be monitored during telaprevir treatment.
o Oral midazolam is increased to a greater extent by telaprevir than intravenous midazolam. Oral midazolam AUC and Cmax were increased 8.96-fold and 2.86-fold, respectively, when combined with telaprevir. Intravenous midazolam AUC was increased 3.4-fold, but Cmax was unchanged. Oral midazolam should not be used with telaprevir, but halving the dose of intravenous midazolam could be considered with monitoring for therapeutic and toxic effects.
o Alprazolam AUC is increased 35% with telaprevir.
o Amlodipine Cmax and AUC are increased 1.27-fold and 2.79-fold by telaprevir, so a reduced dose of amlodipine should be considered in patients on telaprevir.
o Atorvastatin Cmax and AUC are increased 10.6-fold and 7.88-fold by telaprevir. An HMG-CoA reductase inhibitor other than atorvastatin with less potential for interaction (such as rosuvastatin and pravastatin) could be considered for use in combination with telaprevir although neither has been studied to date.
o Ethinyl estradiol concentrations are reduced about 25% with telaprevir with increases in follicle stimulating hormone and luteinizing hormone, so telaprevir may reduce contraceptive efficacy from oral contraceptives containing ethinyl estradiol.
o Zolpidem AUC is reduced 42% by telaprevir, so a higher dose of zolpidem may be required with telaprevir.
A population pharmacokinetic model was developed for boceprevir using 3111 samples obtained during the course of 7 clinical trials. 358 subjects received the commercial formulation of boceprevir at doses ranging from 200 to 1200mg thrice daily with food. A two-compartment model with first-order absorption best characterized boceprevir pharmacokinetics. Age, weight, race, and hepatic and renal function did not significantly predict boceprevir pharmacokinetics, but women had approximately 23% higher boceprevir exposures than men.
Danoprevir, a NS3/4A protease inhibitor in clinical development, is co-administered with a boosting dose of ritonavir. Participants with HCV received an oral cocktail of 2mg midazolam, 10mg warfarin, and 10mg vitamin K before and after 14 days of danoprevir/ritonavir (n=25) or ritonavir alone 100mg every 12 or 24 hours (n=6). Midazolam AUC was increased similarly by danoprevir/ritonavir relative to ritonavir alone (approximately 10-fold) and S-warfarin AUC was reduced similarly by danoprevir/ritonavir relative to ritonavir alone (about 25%). Thus, danoprevir/ritonavir may not have an effect on CYP3A and 2C9 substrates beyond that observed with ritonavir alone, but additional interaction data are needed to confirm.
Polymerase Inhibitors
Combinations of nucleos(t)ide analogs have been a cornerstone of HIV treatment for decades. There may be a similarly important role for nucleos(t)ide analog combinations in the treatment of HCV. PSI-7977 and PSI-938 are nucleotide polymerase inhibitors which undergo intracellular phosphorylation to exert their antiviral effect. PSI-7977 is a uridine analog and PSI-938 is a guanosine analog. PSI-938 concentrations in plasma were compared in 8 patients before and after concomitant administration with PSI-7977 400mg once daily. PSI-7977 concentrations and those of its primary plasma metabolite PSI-6206 were also measured in 8 patients before and after the addition of PSI-938 300mg once daily. The geometric least squares mean AUC and Cmax ratios (90% CI) for PSI-938 with vs. without PSI-7977 were 1.05 (0.9-1.24) and 1.24 (0.84-1.85), respectively. PSI-7977 concentrations were detectable in plasma up to 4 hours post dose, whereas the 6206 metabolite was detectable for the entire 24 hour dosing interval. The geometric least squares mean AUC and Cmax ratios (90% CI) for PSI-7977 with vs. without PSI-938 were 1.53 (1.14-2.04) and 1.54 (1.18-2.19), respectively. The geometric least squares mean AUC and Cmax ratios (90% CI) for PSI-6206 with vs. without PSI-938 were 1.07 (1-1.15) and 1.04 (0.97-1.11), respectively. Thus, there does not appear to be a plasma interaction between the nucleotide polymerase inhibitors PSI-938 and PSI-7977. While the absence of a plasma interaction is re-assuring and an unfavorable intracellular interaction unlikely given that one is a purine and the other a pyrimidine analog, the pharmacologically active moiety of the nucleos(t)ide polymerase inhibitors is the intracellular triphosphate, so studies of this form of the drug would be beneficial for fully characterizing the pharmacology and interaction potential of these drugs. Since obtaining hepatocytes is not possible, peripheral blood mononuclear cells may represent an easily accessible alternative for beginning to characterize phosphorylation patters, half-life, and interaction potential of this drug class in vivo.
Ribavirin
Even in the face of new direct acting antiviral agents, ribavirin will remain an important component of HCV treatment for the foreseeable future. While concentration-effect relationships have been observed for ribavirin, therapeutic drug monitoring (TDM) is not used in clinical practice. One reason that TDM is not used in practice is the lack of well-established ribavirin concentration "cut offs" associated with virologic response. If TDM were to be used for ribavirin, it would need to be implemented before the drug reaches steady state (week 8) because treatment decisions are made before this time (with triple therapy, decisions are made at week 4). Using samples and clinical data from the CIRA study (van Soest H, et al. Dig Liver Dis 2010 Jul;42(7):496-502), David Burger and colleagues (Radbound University Nijmegen Medical Center) found that patients with a ribavirin plasma concentration of less than 2.2 mg/L at week 8 were unlikely to achieve SVR. They then worked backwards to identify concentration "cut offs" at earlier time points so that ribavirin dose adjustments could be implemented earlier in treatment. Minimum effective ribavirin plasma concentrations at weeks 1, 2, and 4 were 0.92 mg/L, 1.29 mg/L, and 1.67 mg/L, respectively. These minimum effective concentrations can be used to examine the utility of ribavirin TDM in optimizing SVR and/or minimizing toxicities in a clinical trial which includes the use of ribavirin with direct acting antiviral agents.
Lambda Interferon
A population pharmacokinetic model was used to determine peginterferon lambda-1 (IL-29) pharmacokinetics in 46 patients receiving the drug in a Phase 2a study. Subjects received 80, 120, 180 or 240 mcg administered subcutaneously once weekly with ribavirin for 48 weeks. A one compartment model with first-order absorption best fit the data. Interferon lambda volume of distribution, apparent oral clearance, half life, and absorption rate constant were 126 L, 33 L/day, 2.9 days, and 3.06 day-1, respectively. Exposures varied by about 60% between subjects. Body weight did not appear to influence dose-normalized exposures. In this same study, the effects of peginterferon lambda and peginterferon alfa on 11 cytokines and chemokines were compared. Both agents stimulated an initial increase in the production of IL-6, IP10 and iTAC relative to pre-treatment values, but IP10 and iTAC production decreased over repeated dosing. Peginterferon alfa 2a also stimulated INF gamma, MCP-1, and MIP-1ß. These data suggest peginterferon lambda may mediate a more restricted immune response than peginterferon alfa as estimated by cytokine production, which may mean fewer flu-like symptoms.
Joint Session with the International Workshop on Hepatitis C, Resistance and New Compounds
Five excellent plenaries were presented in the joint session. While reviewing the clinical trials with HCV protease inhibitors, Stefan Zeuzem (Goethe-University Hospital) raised several thoughtful questions post-telaprevir and boceprevir regulatory approval and discussed the practical issues with these agents that would ideally be overcome with second generation protease inhibitors. Ira Jacobsen (Weill Cornell Medical College) reviewed combination studies and the clinical trials with HCV agents other than protease inhibitors including polymerase and NS5A inhibitors and the cyclophilin antagonist alisporivir. Robert Schooley (University of California San Diego) compared and contrasted HCV and HIV dynamics and replicative fidelity and discussed the implications of dynamics and resistance on HCV drug development. John McHutchison (Gilead Sciences) reviewed the influence of IL28B genetics on response to peginterferon and ribavirin based therapy, discussed the role of IL28B in the era of direct acting antivirals, and the application of genetic discovery to HCV research. Pravin Jadhav (FDA) presented modeling work based on data from 3867 patients which led to the dosing recommendations for prior relapse subjects receiving telaprevir and the approval and dosing recommendations for prior null responders and previously untreated late responders receiving boceprevir.
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