title: Plasma and intracellular exposure to ganciclovir in adult renal transplant recipients: is there an association with haematological toxicity?
abstract: OBJECTIVE
  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.
authors.affiliation: Univ. Limoges, UMR_S 850, F-87000 Limoges, France INSERM, U850, F-87000 Limoges, France p.a@billat.org.
authors.forename: Pierre-André
authors.initials: PA
authors.lastname: Billat
authors.affiliation: 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.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Woillard
authors.affiliation: 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.
authors.forename: Marie
authors.initials: M
authors.lastname: Essig
authors.affiliation: Univ. Limoges, UMR_S 850, F-87000 Limoges, France INSERM, U850, F-87000 Limoges, France.
authors.forename: François-Ludovic
authors.initials: FL
authors.lastname: Sauvage
authors.affiliation: 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.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Picard
authors.affiliation: INSERM, U1092, F-87000 Limoges, France CHU Limoges, Laboratoire de Bactériologie-Virologie-Hygiène, F-87000 Limoges, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Alain
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Neely
authors.affiliation: 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.
authors.forename: Pierre
authors.initials: P
authors.lastname: Marquet
authors.affiliation: 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.
authors.forename: Franck
authors.initials: F
authors.lastname: Saint-Marcoux
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D003586:Cytomegalovirus Infections / Q000188:drug therapy; D003593:Cytoplasm / Q000737:chemistry*; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D016030:Kidney Transplantation; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced*; D010949:Plasma / Q000737:chemistry*; D066027:Transplant Recipients
chemical_list: D000998:Antiviral Agents; D015774:Ganciclovir