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    NATAP http://natap.org/ ... Pharmacokinetic Issues in Hepatitis Coinfection Excerpted from full report: Clinical Pharmacology at CROI 2007 by John Gerber & Jen
    Message 1 of 1 , Mar 20, 2007
      NATAP http://natap.org/


      Pharmacokinetic Issues in Hepatitis Coinfection

      Excerpted from full report: Clinical Pharmacology at CROI 2007 by John Gerber & Jen Kiser (link to full report below)

      Pharmacokinetic Issues in Hepatitis Coinfection
      Hepatic impairment can alter the PK of ARV drugs metabolized by the liver. These data were recently reviewed by one of us (Wyles and Gerber, CID 40:174, 2005). Abstract 946 by Breilh et al. presented Cmax and Cmins for RTV-boosted LPV, ATV, and fAPV, and EFV, and NVP in 113 HIV/Hepatitis C Virus (HCV) coinfected patients. The Cmax and Cmin were compared between patients with a Fibroscan of less than or greater than 12 kPa (which is considered the cut off value for cirrhosis). The Cmax for LPV, ATV, fAPV were obtained at 3, 3, and 2 hours post-observed dose respectively. Neither Cmax nor Cmin differed by liver stiffness score for the RTV-boosted PIs. This is surprising since ATV, LPV/r, and APV AUCs have been shown to be increased in patients with liver dysfunction in previous studies (Reyataz prescribing information, Peng et al. J Clin Pharmacol 46:265, 2006, Lexiva prescribing information). The inability to find a difference in this study in Cmax and Cmin values in patients with and without cirrhosis is likely a result of insufficient power to detect a difference due to the large interpatient variability in Cmin and Cmax concentrations and the small number of subjects on each drug. However Cmin's for EFV and NVP were significantly higher in those patients with Fibroscan scores > 12 kPa. A more intensive PK study in subjects with various stages of liver disease would likely provide a better understanding of the true impact of liver dysfunction on these ARV drugs. (note from Jules Levin: perhaps Fibroscan evaluation of cirrhosis was off).

      Despite many promising investigational therapies against HCV, it is likely that these agents will be used in combination with pegylated interferon and ribavirin in order to limit the development of resistance. Thus, we still need to learn how to optimally dose ribavirin and interferon in order to maximize efficacy and minimize toxicity. Several posters were presented at this year's CROI on TDM of ribavirin and predictors of pegylated interferon/ribavirin treatment success. Ribavirin plasma and erythrocytes Cmins were correlated with virologic response and hemoglobin declines in 22 patients (abstract 893, Dominguez et al.). In a separate study in 42 patients, a ribavirin Cmin of â?¥1600 ng/mL was associated with early and sustained virologic response, while a ribavirin Cmin > 2300 ng/mL seemed to predict toxicity (abstract 903, Marucco et al.)

      ABC-based ARV therapy was identified as a risk factor for failure to achieve an early HCV virologic response in HIV/HCV coinfected patients on pegylated interferon alpha 2b plus ribavirin 800 mg daily (abstract 897, Bani-Sadr, et al.). This is an interesting finding that seems biologically plausible based on the potential pharmacologic antagonism of these drugs, but obviously requires further study (note from Jules Levin: I was taking HAART containing abacavir & tenofovir while on Peg/RBV & achieved undetectable HCV RNA within 5 weeks & SVR, so I'm not sure I believe this abstract. It did not seem like a well done study). Alternatively, TDF or d4T plus 3TC were associated with a higher rate of sustained virologic response to pegylated interferon plus ribavirin (abstract 898, Mira et al.). Two studies found ZDV in combination with ribavirin to be significant predictors of severe toxicity (abstract 902, Nunez et al. and abstract 904, Mira et al.).

      CROI: CLINICAL PHARMACOLOGY AT THE 14TH CROI - Written by John G. Gerber, MD Jennifer J. Kiser, Pharm D (03/13/07)

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