Pharmacokinetic/Pharmacodynamic and Time-to-Event Models of Ribavirin-Induced Anaemia in Chronic Hepatitis C
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Clin Pharmacokinet 2005; 44 (4): 417-428 0312-5963/05/0004-0417/$34.95/0 2005 Adis Data Information BV. All rights reserved.
Pharmacokinetic/Pharmacodynamic and Time-to-Event Models of Ribavirin-Induced Anaemia in Chronic Hepatitis C Michel Tod,1 Muriel Farcy-Afif,2 Jeanick Stocco,2 Nathalie Boyer,3 Val´erie Bouton,2 Martine Sin`egre2 and Patrick Marcellin3 1 2 3
Department of Pharmacy, Cochin-St Vincent de Paul Hospital, Paris, France Department of Pharmacy-Toxicology, Beaujon Hospital, Clichy, France Hepatology Service (INSERM U481 and Centre de Recherche Claude Bernard sur les H´epatites Virales), Beaujon Hospital, Clichy, France
Abstract
Background: Interferon (IFN)-α and ribavirin combination therapy is the standard treatment for patients with chronic hepatitis C. However, ribavirin induces anaemia, especially by haemolysis, an adverse effect that is dose-limiting. Objectives: The aim of this study was to determine the relationships between ribavirin exposure and haemoglobin time-course, the time-to-anaemia and the covariates influencing these relationships in a population of patients treated for chronic hepatitis C. In addition, we also intended to establish a simple rule defining the need for dosage adjustment, using data obtained during the first month of treatment. Methods: A retrospective analysis of 99 patients treated with IFNα plus ribavirin, with known dosage administration history, liver biopsy, demographic data, red blood cell counts, haemoglobin level (1037 measurements, median 10 per patient, range 2–31) and serum creatinine during the entire treatment period (178 days, range 53–382 days) was conducted. The data were analysed by a pharmacokinetic/pharmacodynamic population model and Weibull time-to-anaemia model. The rule defining the need for dosage adjustment was as follows: adjustment was needed if haemoglobin at steady state (Hss), estimated by the Bayesian method based on data obtained during the first month of treatment, was
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