This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hirt, D. Articles by Treluyer, J.-M. Search for Related Content PubMed PubMed Citation Articles by Hirt, D. Articles by Treluyer, J.-M.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, March 2006, p. 910-916, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.910-916.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Age-Related Effects on Nelfinavir and M8 Pharmacokinetics: a Population Study with 182 Children

Pharmacologie Clinique, Assistance Publique—Hôpitaux de Paris,¹ Service de Médecine Neonatale de Port Royal,³ Hôpital Cochin-Saint-Vincent-de-Paul, Université Faculté René Descartes, INSERM,² Service d'Immunologie Pédiatrique, Hôpital Necker-Enfants Malades, Paris, France⁴

Received 29 March 2005/ Returned for modification 2 June 2005/ Accepted 4 December 2005

As a relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established, nelfinavir pharmacokinetics was investigated in order to optimize the individual treatment schedule in a pediatric population. A population pharmacokinetic model was developed to describe the concentration-time course of nelfinavir and its active metabolite M8. Individual characteristics were used to explain the large interindividual variability in children. Data from therapeutic drug monitoring in 182 children treated with nelfinavir were analyzed with NONMEM. Then Food and Drug Administration (FDA) current recommendations were evaluated estimating the percentage of children who reached the target minimum plasma concentration (0.8 mg/liter) by using Bayesian estimates. Nelfinavir pharmacokinetics was described by a one- compartment model with linear absorption and elimination. Pharmacokinetic estimates and the corresponding intersubject variabilities for the model were as follows: nelfinavir total clearance, 0.93 liters/h/kg (39%); volume of distribution, 6.9 liters/kg (109%); absorption rate, 0.5 h^–1; formation clearance fraction to hydroxy-tert-butylamide (M8), 0.025; M8 elimination rate, 1.88 h^–1 (49%). Apparent nelfinavir total clearance and volume of distribution decreased as a function of age. M8 elimination rate was increased by concomitant administration of nevirapine or efavirenz. Our data confirm that the FDA recommendations for children from 2 to 13 years are optimal and that the dose recommended for children younger than 2 years is adequate for the children from 2 months to 2 years old. However, in children younger than 2 months, the proposed nelfinavir newborn dose of 40 mg/kg of body weight twice daily is inadequate and we suggest increasing the dose to 50 to 60 mg/kg administered thrice daily. This assumption should be further evaluated.