A Formula to Estimate the Optimal Dosage of Ribavirin for the Treatment of Chronic Hepatitis C: Influence of Itpa Polymorphisms

Abstract

Greater cumulative exposure to ribavirin increases response to interferon-ribavirin combination therapy for hepatitis C but also induces more severe anaemia. Polymorphisms in the ITPA gene protect against ribavirin-induced anaemia. The maximum dosage of ribavirin that can be tolerated by patients with different ITPA polymorphisms remains unknown. We developed a mathematical model of haemoglobin (Hb) decline in patients undergoing combination therapy. Using it to analyse published patient data, we estimated the average erythrocyte lifespan in patients with different ITPA polymorphisms. Coupled with a previous population pharmacokinetic study, we derived a formula for predicting the optimal ribavirin dosage, D(opt), above which anaemia becomes intolerable (Hb<10 g/dl). Our model provided good fits to patient data of ribavirin accumulation in erythrocytes and the ensuing Hb decline during therapy. With the current treatment protocol, the average erythrocyte lifespan was approximately 36 days in patients with wild-type ITPA activity, and approximately 43 days and 55 days, respectively, in patients with mild and moderate ITPA deficiency. Our model yielded a facile formula for estimating D(opt) given a patient's weight, creatinine clearance, pretreatment Hb and ITPA polymorphism. Patients with moderate ITPA deficiency are predicted to tolerate twice the ribavirin dosage as patients with wild-type ITPA. Our formula for D(opt) presents an avenue for personalizing ribavirin dosage. By keeping anaemia tolerable, the predicted optimal dosage may improve adherence, reduce the need for drug monitoring, and increase response rates. Response rates may be increased further by the higher dosages recommended for patients with ITPA deficiency.