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J Antimicrob Chemother. 2016 Feb;71(2):484-9. doi: 10.1093/jac/dkv342. Epub 2015 Nov 3.

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

Author information

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.

PMID:
26538506
DOI:
10.1093/jac/dkv342
[Indexed for MEDLINE]

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