A formula to estimate the optimal dosage of ribavirin for the treatment of chronic hepatitis C: influence of ITPA polymorphisms.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Ribavirin-induced anemia in hepatitis C virus patients undergoing combination therapy.

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.

Estimation of red blood cell lifespan from alveolar carbon monoxide measurements.

Measurement of alveolar carbon monoxide (CO) presents a facile technique to estimate the lifespan, L, of red blood cells (RBCs) in vivo. Several recent studies employ this technique and calculate L (in days) using the expression, L=13.8 [Hb]/P(CO)(end), where [Hb] is the concentration (in g/dL) of hemoglobin in blood, and P(CO)(end) is the endogenous production of CO (in ppm). Implicit in this calculation is the assumption that the fraction, f, of endogenous CO production due to RBC turnover is a constant equal to 0.7, which yields the expected RBC lifespan, L approximately 120 days, in normal controls. In anemic patients, however, enhanced RBC turnover may increase f substantially above 0.7. The above expression then overestimates L. Here, we derive an alternative expression, L=3390[Hb]/322P(CO)(end)-110, that accounts explicitly for the dependence of f on the rate of RBC turnover and thereby provides more accurate estimates of L without requiring additional measurements. Using the latter expression, we recalculate L from recent measurements on hepatitis C virus infected patients undergoing treatment with ribavirin. We find that our estimates of L in these patients (39+/-13 days) are significantly lower than current estimates (46+/-14 days), indicating that ribavirin affects RBC survival more severely than expected from current studies. Our expression for L is simple to employ in a clinical setting and would render the broadly applicable technique of alveolar CO measurement for the estimation of RBC lifespan more accurate.