| Ribavirin is an important component of the treatment regimens for hepatitis C virus (HCV) genotype 1 infection. New HCV direct acting antiviral drugs in clinical stages of development still require co-administration of ribavirin, despite its well-known side effect of hemolytic anemia. The overall goal of this work is to develop a model relating ribavirin dose to systemic and intracellular exposure, and to toxicity (anemia) and drug response (viral load), to both better understand the mechanism of ribavirin action and as a basis for guiding individualization of ribavirin therapy.;The plasma pharmacokinetic model revealed that ribavirin had a terminal elimination half-life of around 224 hours, and there was no evidence of time-dependent kinetics. The phosphorylation model revealed that RMP, RDP and RTP were in rapid equilibrium. The turnover half-life was estimated to be 65 minutes in PBMC and 36 hours in RBC. However, because the intracellular half-lives are much faster than the plasma elimination half-life, the phosphorylated ribavirin moieties exhibit a flip-flop phenomenon and the same apparent half-life as that of ribavirin in plasma.;The ribavirin-induced anemia model incorporated the physiological understanding of RBC lifespan, the effect of RTP on increasing RBC loss rate, and the feedback mechanism through the hormone erythropoietin that regulates the RBC production rate in response to anemia. The model reliably predicts the reduced RBC lifespan and feedback response. New insights into the effect of ITPA and IL28B polymorphism on ribavirin-induced anemia model were also revealed.;The viral dynamic model incorporated the enhanced viral response seen with the co-administration of telaprevir and IL28B CC genotype. Given the objectives of the clinical study and its design, however, we could not independently determine the contribution of treatment effect of Peg-IFN alpha, ribavirin and telaprevir.;In conclusion, we have utilized quantitative systems modeling approaches to gain insight into ribavirin plasma pharmacokinetics, its intracellular kinetics in PBMCs and RBCs, ribavirin-induced anemia and viral responses, as well as the influence of pharmacogenetic and clinically relevant covariates on these processes. This model framework provides an important foundation for investigating new subgroup treatment strategies and individually targeted therapy to maximize SVR and minimize the incidence of anemia in treatment regimens that include ribavirin. |
