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Modeling Ribavirin-Induced Anemia in Patients with Chronic Hepatitis C Virus.

ABSTRACT: Ribavirin remains an important component of hepatitis C treatment in certain clinical scenarios, but it causes hemolytic anemia. A quantitative understanding of the ribavirin exposure-anemia relationship is important in dose individualization/optimization. We developed a model relating ribavirin triphosphate (RTP) exposure in red blood cells (RBCs), RBC lifespan, feedback regulation of RBC production when anemia occurs, and the resulting hemoglobin decline. Inosine triphosphatase (ITPA) and interleukin 28B (IL28B) genetics were found to be significant covariates. Clinical trial simulations predicted that anemia is least severe in IL28B non-CC (rs12979860, CT or TT), ITPA variant subjects, followed by IL28B non-CC, ITPA wild-type, IL28B CC, ITPA variant, and IL28B CC, ITPA wild-type subjects (most severe). Reducing the ribavirin dose from 1,200/1,000 mg to 800/600 mg could reduce the proportions of grade 2 anemia by about half. The resulting model framework will aid the development of dosing strategies that minimize the incidence of anemia in treatment regimens that include ribavirin.

SUBMITTER: Wu LS

PROVIDER: S-EPMC4761234 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Modeling Ribavirin-Induced Anemia in Patients with Chronic Hepatitis C Virus.

Wu L S LS Jimmerson L C LC MacBrayne C E CE Kiser J J JJ D'Argenio D Z DZ

CPT: pharmacometrics & systems pharmacology 20160202 2

Ribavirin remains an important component of hepatitis C treatment in certain clinical scenarios, but it causes hemolytic anemia. A quantitative understanding of the ribavirin exposure-anemia relationship is important in dose individualization/optimization. We developed a model relating ribavirin triphosphate (RTP) exposure in red blood cells (RBCs), RBC lifespan, feedback regulation of RBC production when anemia occurs, and the resulting hemoglobin decline. Inosine triphosphatase (ITPA) and inte ...[more]

PMID: 26933517

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Project description:The current standard of care for hepatitis C virus (HCV) infection - combination therapy with pegylated interferon and ribavirin - elicits sustained responses in only ?50% of the patients treated. No alternatives exist for patients who do not respond to combination therapy. Addition of ribavirin substantially improves response rates to interferon and lowers relapse rates following the cessation of therapy, suggesting that increasing ribavirin exposure may further improve treatment response. A key limitation, however, is the toxic side-effect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus requires striking a balance between the antiviral and hemolytic activities of ribavirin. Current models of viral kinetics describe the enhancement of treatment response due to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and precludes rational optimization of combination therapy. Here, we develop a new mathematical model of the population dynamics of erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients. Based on the assumption that ribavirin accumulation decreases erythrocyte lifespan in a dose-dependent manner, model predictions capture several independent experimental observations of the accumulation of ribavirin in erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy, estimate the reduced erythrocyte lifespan during therapy, and describe inter-patient variations in the severity of ribavirin-induced anemia. Further, model predictions estimate the threshold ribavirin exposure beyond which anemia becomes intolerable and suggest guidelines for the usage of growth hormones, such as erythropoietin, that stimulate erythrocyte production and avert the reduction of ribavirin dosage, thereby improving treatment response. Our model thus facilitates, in conjunction with models of viral kinetics, the rational identification of treatment protocols that maximize treatment response while curtailing side effects.

Dataset Information

Modeling Ribavirin-Induced Anemia in Patients with Chronic Hepatitis C Virus.

Publications

Modeling Ribavirin-Induced Anemia in Patients with Chronic Hepatitis C Virus.

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