Plasma and intracellular exposure to ganciclovir in adult renal transplant recipients: is there an association with haematological toxicity?

Ganciclovir is the most widely used treatment for cytomegalovirus infections. However, neutropenia is a frequent associated adverse effect leading to a decrease in the ganciclovir dose or discontinuation of the therapy, thereby favouring viral resistance. In the present study, the objectives were: (i) to describe the pharmacokinetics of blood and intracellular ganciclovir and its metabolites; and (ii) to explore the relationship between exposure to ganciclovir and/or its metabolites and evolution of the neutrophil count under treatment. Pharmacokinetic profiles (pre-dose and 1, 2, 3 and 5 h after dosing) of ganciclovir and its metabolites were measured in 22 adult renal transplant patients and further modelled by a non-parametric approach (PMetrics(A (R))). The relationship between exposure indices to ganciclovir and the slope of the neutrophil count was investigated using multiple linear regression. A four-compartment open model was able to accurately describe ganciclovir and its intracellular forms. A significant association was found between intracellular ganciclovir triphosphate concentrations (AUC(0-5)) and the decrease in neutrophil count over the first 3 months of treatment (beta aEuroS=aEuroSa'0.0019aEuroS +/- aEuroS5aEuroSxaEuroS10(-4); PaEuroS < aEuroS0.01). In this population of renal transplant patients, the decrease in neutrophil count, used as a surrogate marker of haematological toxicity, was associated with ganciclovir triphosphate accumulation in blood cells. Further studies are needed to test this biomarker as a predictive factor for toxicity.