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Meeting Report - 5th International Workshop on Clinical Pharmacology of Hepatitis Therapy - by Jennifer Kiser PharmD
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Boston, MA
June 23-24, 2010
Jennifer Kiser, PharmD
Assistant Professor
University of Colorado Denver
The International Workshop on Clinical Pharmacology of Hepatitis Therapy 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. With the impending approval of direct acting antiviral (DAA) drugs for chronic Hepatitis C virus (HCV), a significant appreciation for the clinical pharmacology of these agents will be imperative to optimize their use and improve treatment outcomes.
This report does not cover all lectures and data presented at the Workshop. For more information or to view additional presentations from the meeting visit www.virology-education.com.
FDA and EMA Perspectives on DAA Combination Studies
Jeff Murray (FDA) offered his perspective on early clinical testing of novel HCV agents. The FDA encourages DAA combination studies when prerequisite data are available (see Dr. Murray's slide on "use of two or more DAAs, prerequisite data" at www.natap.org). Possible designs for initial combination trials include 1) short duration (<2 weeks) in naïve patients followed by peginterferon and ribavirin with or without one or more of the DAAs, 2) longer durations with frequent HCV RNA monitoring and stopping rules, and 3) in the setting of liver transplantation. Dr. Murray issued a call to action to study DAAs in liver transplant patients; stating that even a small pilot study could potentially support efficacy in this population in package labeling. Because there are feasibility challenges in this population, Dr. Murray suggested use of a historical control and real-time therapeutic drug monitoring to assess appropriateness of DAA and immunosuppressant doses. The FDA will issue a draft of a new guidance on multidrug combination studies for several diseases (e.g., tuberculosis, cancer, and HCV) in the fall 2010.
The EMA will also issue a draft of revised guidance for HCV drug development later this year. The revised guidance will hopefully address combination DAA studies with and without standard of care and studies and labeling requirements for special populations (e.g., transplant, HIV coinfection, decompensated disease, etc.). Jean-Michel Pawlotsky (Henri Mondor Hospital) reviewed the current EMA guidance for HCV drug development. He also challenged whether all the stakeholders involved in HCV drug development - researchers, regulatory agencies, and companies - had done their best to date to protect patients, given potentially efficacious compounds a fair chance at development, and conducted well designed trials. While these questions are difficult to answer, they are important to consider, since we all share a common goal of curing as many persons with HCV as possible.
Pharmacokinetic Enhancers for HCV Protease Inhibitors (PIs)
Minimizing pill burden and dosing frequency are desirable characteristics for the treatment of any condition and this can be accomplished with pharmacokinetic enhancers (PKE or "boosters"). However, these benefits must be carefully balanced against the challenges of PKE which may include additional toxicities and greater drug interaction potential.
· Ritonavir boosting significantly improved the pharmacokinetic profiles of HIV PIs, allowing for lower doses, less frequent administration, and higher trough concentrations which enhanced efficacy. Dale Kempf (Abbott) reviewed data on the use of ritonavir as a booster of the HCV PIs narlaprevir (SCH900518), danoprevir (ITMN-191/RG7227), and ABT-450. Improvements in PK resulted in greater efficacy of ritonavir boosted narlaprevir and danoprevir regimens compared to unboosted regimens. Studies of boosted vs. unboosted ABT-450 suggest ritonavir may boost by accessory mechanisms (beyond blocking CYP3A) including inhibition of the drug transporters P-glycoprotein, breast cancer resistance protein, and multidrug resistance protein 2.
· Cobicistat (formerly GS-9350) has not been evaluated as a pharmacokinetic enhancer of HCV drugs.
Ribavirin - Still Needed, but How Does it Work?
Ribavirin will remain an important component of combination regimens for the treatment of HCV for the foreseeable future. Thus, it is important to elucidate its mechanism of action. Jordan Feld (Toronto Western Hospital Liver Center) reviewed the available data on ribavirin's postulated mechanisms of action. His interpretation of available evidence suggests ribavirin is not a direct antiviral agent and that it is needed both early in treatment to prevent development of resistance and later in treatment to prevent relapse. In terms of an early effect, ribavirin may induce interferon signaling genes and improve second phase kinetics, but it doesn't appear useful when interferon works really well or when interferon doesn't work at all. Mutagenesis may be relevant for the early and late effects of the drug by limiting quasi-species diversity and limiting "escape potential". Data from studies of regimens of ribavirin plus DAAs with and without interferon will offer additional insight on the mechanisms of action of this drug.
Joint Session with the Workshop on Hepatitis C, Resistance and New Compounds
As in 2009, a joint session was held with the International Workshop on Hepatitis C, Resistance and New Compounds. There are many shared interests between meeting participants and four lectures highlighted topics important to both groups.
· Mark Sulkowski (Johns Hopkins University) spoke to the implications of host genetics for HCV drug development and patient care. He demonstrated that stratification of participants based on IL28B genetics is important for small trials and that an imbalance has major implications for study results. A commerical test for IL28B genetics will be available by the middle of July 2010.
· Gary Davis (Baylor University Medical Center) described how the maturation of the HCV-infected patient population will impact society and pharmaceutical drug development. He stressed how many persons with HCV are unfortunately undiagnosed. However, HCV-related liver complications are expected to peak in 2020, thus the optimal time to treat this disease is now.
· Charlie Rice (The Rockefeller University) reviewed how technological advances in cell culture and humanized xenograft murine models provided insights into HCV entry, translation, replication, and assembly, which revealed new viral and cellular targets for HCV drug discovery efforts. The pros and cons of developing viral vs. host targets were reviewed.
· Jean Michel Pawlotsky (Henri Mondor Hospital) discussed the dynamics of resistance and the implications for HCV drug development. The main drivers of drug resistance are baseline pre-existing mutations, secondary mutations, and drug exposure. The latter being particularly relevant for clinical pharmacology researchers since incorrect doses or dosing frequencies or unexpected drug-drug interactions could lead to the development of resistance.
Selected Original Research Presentations
Peginterferon alfa 2a
PROGRESS (Reddy AASLD 2009) evaluated induction peginterferon doses (360 mcg per week for 12 weeks) and ribavirin doses ranging from 1200-1600 mg daily in genotype 1 previously treatment naïve persons having HCV RNAs of at least 400,000 copies/mL and weighing at least 85 kg. Peter Morcos (Roche) reported that in a subset of 46 patients from the PROGRESS study, early viral declines appeared enhanced with higher peginterferon doses. It is unclear to what degree the ribavirin doses contributed to this finding. Concentration-toxicity relationships were not explored.
Ribavirin
· Jennifer Kiser (University of Colorado Denver) presented an assay for measuring intracellular ribavirin mono- (RBV-MP), di- (RBV-DP), and triphosphate (RBV-TP) concentrations in peripheral blood mononuclear (PBMCs) and red blood cells (RBCs) and showed concentration results from patients with HCV receiving ribavirin as part of their treatment. Intracellular RBV-MP plus RBV-DP plus RBV-TP concentrations were 5 fold higher in RBCs than PBMCs. There was also greater variability in RBV-MP, RBV-DP, and RBV-TP concentrations in RBCs than PBMCs. While in PBMCs RBV-TP was the predominant analyte, this was not the case in RBCs. This new analytical methodology can be applied to fully characterize the clinical pharmacology of intracellular ribavirin.
· Klaartje de Kanter (Radboud University Nijmegen Medical Center) found that in a retrospective look at their therapeutic drug monitoring database, more HIV/HCV coinfected patients had plasma ribavirin concentrations less than 2 mg/L than did HCV-monoinfected patients. The mechanism for this is unclear, but could relate to differences in sampling time post-dose, drug interactions with antiretroviral drugs, or adherence.
Telaprevir
· Telaprevir pharmacokinetics were unaffected by esomeprazole. Thus, telaprevir absorption is not affected by changes in gastric acid pH and should be safe for concomitant use with gastric acid modifiers like antacids, proton pump inhibitors, and H2 receptor antagonists.
· Escitalopram (Lexapro) exposures are reduced an average of 35% by telaprevir. There are no obvious concentration-effect data for the selective serotonin reuptake inhibitors (SSRIs), so it is unknown if this reduction would translate into reduced ability to control depressive symptoms. However, considering the slow onset of action of anti-depressants, the prudent course may be to use higher SSRI doses in patients on telaprevir. The mechanism for this interaction is unclear. Telaprevir may induce CYP2C19 or 3A which are the major routes of metabolism for escitalopram.
Filibuvir
Filibuvir, a nonnucleoside polymerase inhibitor, is 98% protein bound, a substrate for CYP3A4, and is 17% really eliminated. Following 14 days of filibuvir 300mg twice daily dosing in HCV seronegative volunteers, participants ages 65-74 and 75-85 had filibuvir area under the concentration time curves (AUCs) 133 and 123% higher, respectively than subjects 18-55 years. Terminal half lives were 9.13, 12.2, and 14.2 hours in those ages 18-55, 65-74, and 75-85 years, respectively. Following a single 200mg dose in the fasted state, subjects with moderate hepatic impairment (Child Pugh B) had filibuvir AUCs 2.3-fold higher than those with normal hepatic function. Filibuvir is in Phase IIb trials.
An understanding of the clinical pharmacology of drugs is essential to optimally treating a disease. Thus, as DAAs reach the marketplace and DAA combination regimens become the standard of care for HCV, I anticipate this Workshop will continue to grow in attendance and scope of presented material. The field of viral hepatitis needs more pharmacokinetic-dynamic, pharmacokinetic-genetic and drug-drug interaction studies and studies of antiviral pharmacokinetics in "special" patient populations.
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