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The 3rd International Workshop on Clinical Pharmacology of Hepatitis Therapy
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New Orleans April 6, 2008
Jennifer J. Kiser, Pharm.D.
Assistant Professor
University of Colorado Denver
jennifer.kiser@uchsc.edu
Abbreviations/Definitions
ACTG, AIDS Clinical Trials Group
AIDS, acquired immunodeficiency syndrome
ARV, antiretroviral drug
Cmin, minimum concentration
EVR, early virologic response: greater than or equal to a 2-log drop or loss of HCV RNA at 12 weeks into therapy
HIV, human immunodeficiency virus
HCV, Hepatitis C Virus
HCV RNA, Hepatitis C viral load
Non-responder: less than a 1 log decrease in HCV RNA at week 12
NRTI, nucleos(t)ide reverse transcriptase inhibitor
Partial responder: greater than a 1 log decrease in HCV RNA at week 12, but detectable at week 24
PBMC, peripheral blood mononuclear cells
PegINF, peginterferon
PD, pharmacodynamics
PK, pharmacokinetics
PIs, protease inhibitors
Relapser: undetectable HCV RNA at the end of treatment, but return of HCV RNA after cessation of treatment
RBC, red blood cells
RBV, ribavirin
RVR, rapid virologic response: undetectable HCV RNA after 4 weeks of treatment
SOC, standard of care, presently peginterferon and ribavirin
SVR, sustained virologic response: undetectable viral load 24 weeks after the cessation of treatment
The 3rd International Workshop on the Clinical Pharmacology of Hepatitis Therapy was held April 9-10, 2008 in New Orleans, Louisiana. This year's meeting followed the 9th International Workshop on Clinical Pharmacology of HIV Therapy which allowed for a joint session with attendees of both workshops on the afternoon of April 9. Four plenaries during the joint session covered several issues related to drug development and treatment of HIV and viral hepatitis.
Dr. Avidan Neumann (Bar-Ilan University) discussed the role of mathematical modeling of viral dynamics in the development of new antiviral compounds. Dr. Neumann demonstrated the role of models in understanding HCV infection and replication, providing insight into the mechanisms of action of PegINF and RBV and the time course of response to therapy, and evaluating antiviral dynamics and resistance evolution with investigational HCV compounds. These mathematical models will undoubtedly be useful tools for understanding the mechanisms of action of therapies, resistance evolution patterns, determining optimal treatment durations, and for early prediction of response to therapy.
Dr. David Thomas (Johns Hopkins University) reviewed treatment strategies for HIV/HCV coinfected patients during the joint session. He reminded the audience that liver disease was the number one cause of non-AIDS related deaths in persons with HIV and that the treatment of HCV was in "asystole" (i.e. nothing has changed) since PegINF and RBV have been our SOC for seven years. He illustrated how few patients (~6%) were actually eligible for HCV treatment and stressed that access to therapy needed to be as important a focus as the development of new compounds.
Dr. Kimberly Struble (FDA Division of Antiviral Products) provided guidance on trial design with investigational HCV compounds. She stressed that for studies evaluating treatments of different durations, the primary endpoint (SVR) should be assessed for all treatment groups 24 weeks after discontinuing treatment in the group with the longest treatment duration. Additionally, the FDA prefers that investigational compounds be added to SOC, though alternative designs would be considered in more difficult to treat populations or in those patients with contraindications to the SOC. If two novel compounds are being evaluated, each should be evaluated in combination with the SOC, against the SOC, and then a fourth arm could include SOC plus both investigational agents. Monotherapy trials should be of very limited duration. Lastly, she reminded the audience that the patient populations with greatest need for study are those with prior non-response, partial response, or relapse and that new compounds should be investigated in this setting when possible. Drs. Struble, Kellie Reynolds (FDA), Janet Hammond (Valeant Pharmaceuticals), and Charles Flexner (Johns Hopkins University) facilitated a round table discussion to address several of the topics raised during Dr. Struble's presentation. This forum greatly facilitated the dialogue between the FDA representatives and researchers from industry and academia on how to most efficiently conduct studies with investigational compounds.
Dr. Paul Watkins (University of North Carolina at Chapel Hill) discussed drug induced liver injury and the implications for development of new compounds for HIV and viral hepatitis. Hepatotoxicity is the most common adverse drug reaction. However, it is very difficult to predict early in drug development which compounds may cause hepatotoxicity because there are no validated strategies to assess for hepatotoxicity. Furthermore, the "screens" presently used are largely ineffective. He discussed the research initiatives of the drug-induced liver injury network and the critical importance of collecting clinical data and biological specimens in clinical trials when a liver safety issue is identified.
The second day of the Workshop featured several invited lectures and original research presentations. Dr. Thomas presented on the epidemiology of HCV in the developing world. While very few new infections are occurring in the United States, new infections continue in the rest of the world primarily due to unsafe medical procedures (e.g., re-use of injections and syringes). Dr. Thomas showed that of the 16 billion injections given annually world-wide, 6.7 billion were unsafe and that efforts were desperately needed to reduce this practice and prevent the spread of new infections.
Dr. Terrence Blaschke (Stanford University) shared with the audience some challenges faced in the global drug development of ARV drugs. A major issue is counterfeit drugs. An estimated 10-30% of drugs circulating in the world are counterfeit, and this is a particular problem for antibiotics and antivirals. There have also been challenges in the HIV arena with making co-formulated products including the difficulty in getting compounds from different biochemical classes into one pill, getting pharmaceutical companies to work together to develop these products, and an inability to titrate the dose of the individual components which is of particular concern for treating pediatric patients. He also reviewed adherence data and discussed the pros and cons of once daily vs. multiple times daily dosing of antiviral drugs.
Dr. Richard Kim (University Hospital W. Ontario) discussed the role of hepatic transporters in the uptake of drugs into the liver and efflux of drugs into the bile, the impact of polymorphisms in the genes encoding hepatic drug transporters on substrates PK and PD, and the role of drug transporters in drug-drug interactions and toxicity. He stressed that a compound's affinity for various transporters, and its ability to inhibit or induce transporters should be determined early in drug development because this has important implications for determining a compound's PK, efficacy, and toxicity.
Dr. William Symonds (Pharmasset) reviewed the many considerations and challenges for implementing and conducting clinical trials world-wide. The issues ranged from those involved in setting up the studies (e.g., use of several local vs. one central laboratory, the variation in regulatory approvals by country, and the requirement for the study documents to be available in multiple languages) to those involved with the conduct of global clinical trials (e.g., the variation in management of adverse events by country, recruitment, and safety reporting).
Original research presentations are reviewed below and divided into two categories - Investigational Hepatitis C Therapeutics and Concentration-Effect Studies with Ribavirin.
Investigational Hepatitis C Therapeutics
Dr. John McCauley (Merck) presented PK and preliminary efficacy data with MK-7009, a novel HCV PI, in animals. In both rats and chimpanzees, liver exposures were significantly greater than plasma exposures following oral dosing. After seven days of MK-7009 monotherapy at 5 mg/kg twice daily, two chimpanzees had viral load reductions of greater than 5 logs, and they remained suppressed over the course of dosing. Furthermore, when MK-7009 was given in combination with an investigational Merck polymerase to 3 chimpanzees for 36 days, followed by 48 days of MK-7009 monotherapy, one of the chimpanzees achieved SVR. MK-7009 has moved into human clinical trials.
Bocepravir (SCH-503034) is an HCV PI in Phase IIb trials. Dr. Eric Hughes (Schering-Plough) presented a study evaluating the effect of bocepravir on QT/QTc prolongation in healthy volunteers. QT/QTc prolongation was assessed in 36 healthy volunteers in a four way crossover which included bocepravir at a therapeutic dose of 800 mg three times daily, a supratherapeutic bocepravir dose of 1200 mg three times daily, moxifloxacin 400 mg as a control, and placebo. Both bocepravir doses were similar to placebo in mean change in QTcF (QTcB, QTcl, and uncorrected QT interval results were concordant with QTcF analysis). Thus, bocepravir does not prolong the QTc interval. The most common adverse events in subjects on bocepravir were nausea, headache, and taste perversions.
Concentration-Effect Studies with Ribavirin
It has become increasingly evident from recent studies that RBV cannot simply be replaced with newer compounds. Instead, RBV will continue to be an integral component of Hepatitis C treatment for several years to come. Thus, there is still a great need to define the pharmacology of this drug and determine if there are potential strategies to optimize its therapeutic effects. Three abstracts were presented at the meeting which investigated concentration-effect relationships for RBV.
Dr. Almasi (Cochin Hospital) presented a small, concentration-guided RBV dosing study in HIV/HCV coinfected patients. Twenty patients on RBV doses from 800-1200 mg had a serum RBV level obtained after 4 weeks on treatment between 10.8-16 hours post-dose (doses were not observed). Those patients with a RBV concentration less than 2.2 mcg/mL had their RBV doses increased by 200 mg (max dose however was 1200 mg). 13 of the 20 patients had RBV concentrations below 2.2 mcg/mL at week 4, and 9 of these 13 had their RBV doses increased. Four of these 9 patients had achieved the 2.2 mcg/mL target serum concentration by week 8. A relationship between RBV trough levels and EVR or SVR was not detected, but those with RBV concentrations greater than 2.2 mcg/mL had a mean hemoglobin decline of 2.46 g/dL vs. only 1.6 g/dL in those with RBV concentrations less than 2.2 mcg/mL.
Dr. Caroline Solas (Hospital de la Timone) evaluated the relationship between RBV Ctrough at week 4 and RVR in 25 HIV/HCV coinfected patients. RBV doses ranged from 400-1000 mg daily. Six patients had a RBV Ctrough greater than 2.5 mcg/mL at week 4 and the remaining 19 had a RBV Ctrough of less than 2.5 mcg/mL. Three of the six patients with week 4 RBV Ctroughs greater than 2.5 mcg/mL achieved an RVR vs. none with RBV Ctroughs less than 2.5 mcg/mL. Six patients were also on abacavir and they compared RBV plasma concentrations between those on abacavir vs. those on other NRTI and there were no differences, however this does not rule out the possibility of an intracellular interaction between RBV and abacavir that might explain what appears to be a decreased SVR rate in patients on abacavir plus ribavirin vs. other NRTI.
Dr. Gilles Peytavin (Hospital Bichat-Claude Bernard) determined plasma RBV Cmin and total RBV RBC concentrations at week 4 in 68 HIV/HCV coinfected patients and evaluated the relationships between these concentrations and EVR, SVR, and hemoglobin decline. A receiver operating characteristic (ROC) curve (determines the sensitivity of a particular threshold value for predicting an outcome) was also used to determine RBV concentration "cut-offs" that may be associated with EVR, SVR, and hemoglobin decline. RBV doses ranged from 800-1200 mg daily. In patients with genotype 1 and 4 virus, the ROC curve showed that EVR and SVR was more likely to occur in patients with RBV Cmin > 1.95 mcg/mL and RBV RBC concentrations > 146 mg/L at week 4. No RBV RBC concentration "cut off" was identified for determining declines in hemoglobin. However, the concentrations in these RBC reflect total RBV concentrations (the combination of RBV mono-, di-, and triphosphorylated anabolites), so additional work in this area is needed.
As with much of the previously published data in this area, these studies contained small patient numbers with sparse sampling of plasma or serum RBV concentrations which were likely obtained prior to patients achieving RBV steady-state (the RBV plasma half-life is over 12 days, so steady-state would presumably not be reached until almost 9 weeks). Furthermore, the target RBV concentrations between these studies are inconsistent because definitive "target" RBV concentrations have not been established. Theoretically, we will need to understand the intracellular concentration target - as this is the pharmacologically active form - rather than a serum or plasma target. Work in this area remains important because we will continue to use RBV for the treatment of Hepatitis C for the foreseeable future. Future studies should contain larger patient numbers with more intensive PK sampling, including intracellular quantification of RBV anabolites.
In closing, a positive and unique feature of the Hepatitis PK Workshop is the multidisciplinary representation. Individuals from industry, academia, clinical practice, and the FDA were in attendance. This meeting recognizes the role that each of these entities plays in advancing the care of patients infected with chronic viral hepatitis. Several exciting topics have already been slated for the 4th International Workshop on Clinical Pharmacology of Hepatitis Therapy, which is expected to be held in conjunction with the 4th International Workshop on Hepatitis C, Resistance, and New Compounds.
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