Stéphane Mouly(1), Saik Urien(2), Jean-Paul Tillement(2), Jean-François Bergmann(1), and Charles Caulin(1)
1)Département de Médecine Interne et Thérapeutique, Hopital Lariboisière, Paris; 2) Laboratoire de Pharmacologie, Faculté de Médecine, Université Paris XII, 94010 Créteil, France
Oral gancyclovir is a poorly absorbed antiviral drug (F ~ 6-9%). It is used in cytomegalovirus infection prophylaxis during HIV infection. The effect of diarrhea on gancyclovir bioavailabily is unknown since pharmacokinetic studies always excluded patients with diarrhea. In order to investigate this problem, we conducted a prospective clinical pharmacology study in which 42 HIV-infected patients were enrolled and divided into 3 groups according to the presence or absence of diarrhea and weight loss: (A) HIV asymptomatic without diarrhea and weight loss, (B) AIDS patients without diarrhea and weight loss and (C) AIDS patients with diarrhea (defined as 3 loose bowel movements a day for at least 3 weeks and/or weight loss). Complete clinical examination, nutritional and immunological status were recorded: sex, weight, age, body mass index; albumin, transferrin, haptoglobin, creatinin, hemoglobin concentrations; CD4 count, viral load. The pharmacokinetic study was performed after an overnight fast. Each patient took 1 g of gancyclovir and 6 blood samples were drawn between 0.5 h and 24 h after ingestion. Plasma gancyclovir concentration was determined by HPLC with fluorescence detection.
Data analysis was performed by using a non linear mixed effect model program, MP2. Gancyclovir kinetics after oral administration was best described by a one-compartment open model with first order input. Inter-individual and residual variabilities were ascribed to a proportional error model. In the final model, the clinical status (C group versus others) significantly affected the model parameters, volume of distribution (Vd), clearance (CL) and absorption rate constant (Ka). Additionally, CL was related to the log(CD4 count) and hemoglobin blood level, and Ka was related to the plasma haptoglobin concentration. The incorporation of these covariates in the pharmacokinetic modelling of gancyclovir allowed to strongly decrease the inter-individual variability of CL (from 97.2% to 42.2%). When the clinical status alone was incorporated in the clearance modelling, the clearance in the group C patients was 60% decreased (corresponding to an increased AUC) as compared to groups A and B, and the CL inter-individual variability was 46.3%.
These results show that diarrhea dramatically improved oral gancyclovir bioavailability in HIV-infected patients probably because of an increased intestinal permeability. Oral dosage of gancyclovir in these patients should be reduced to achieve a drug exposure similar to that obtained in non-diarrheic HIV-infected patients.
Reference: PAGE 8 (1999) Abstr 163 [www.page-meeting.org/?abstract=163]
Poster: poster