Pierre-André Billat1, Jean-Baptiste Woillard2, Marie Essig3, François-Ludovic Sauvage4, Nicolas Picard2, Sophie Alain5, Michael Neely6, Pierre Marquet2, Franck Saint-Marcoux2. 1. Univ. Limoges, UMR_S 850, F-87000 Limoges, France INSERM, U850, F-87000 Limoges, France p.a@billat.org. 2. Univ. Limoges, UMR_S 850, F-87000 Limoges, France INSERM, U850, F-87000 Limoges, France CHU Limoges, Service de Pharmacologie, Toxicologie et Pharmacovigilance, F-87000 Limoges, France. 3. Univ. Limoges, UMR_S 850, F-87000 Limoges, France INSERM, U850, F-87000 Limoges, France CHU Limoges, Service de Néphrologie, Dialyse et Transplantation, F-87000 Limoges, France. 4. Univ. Limoges, UMR_S 850, F-87000 Limoges, France INSERM, U850, F-87000 Limoges, France. 5. INSERM, U1092, F-87000 Limoges, France CHU Limoges, Laboratoire de Bactériologie-Virologie-Hygiène, F-87000 Limoges, France. 6. University of Southern California, Keck School of Medicine, Los Angeles, CA, USA Laboratory of Applied Pharmacokinetics and Bioinformatics (LAPKB), Children's Hospital of Los Angeles, Los Angeles, CA, USA.
Abstract
OBJECTIVES: 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. METHODS: 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(®)). The relationship between exposure indices to ganciclovir and the slope of the neutrophil count was investigated using multiple linear regression. RESULTS: 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 (AUC0-5) and the decrease in neutrophil count over the first 3 months of treatment (β= -0.0019 ± 5 × 10(-4); P < 0.01). CONCLUSIONS: 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.
OBJECTIVES: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. METHODS: 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(®)). The relationship between exposure indices to ganciclovir and the slope of the neutrophil count was investigated using multiple linear regression. RESULTS: 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 (AUC0-5) and the decrease in neutrophil count over the first 3 months of treatment (β= -0.0019 ± 5 × 10(-4); P < 0.01). CONCLUSIONS: 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.
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