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Antimicrobial Agents and Chemotherapy, October 2009, p. 4407-4413, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.01594-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Is the Recommended Dose of Efavirenz Optimal in Young West African Human Immunodeficiency Virus-Infected Children?{triangledown} ,{ddagger}

Déborah Hirt,1,2* Saik Urien,1,2 Mathieu Olivier,3 Hélène Peyrière,3 Boubacar Nacro,4 Serge Diagbouga,5 Emmanuelle Zoure,4,5 François Rouet,5,6 Hervé Hien,5,6 Philippe Msellati,6 Philippe Van De Perre,7 and Jean-Marc Tréluyer1,2,8

EA3620,1 Service de Pharmacologie Clinique, AP-HP, Hôpital Cochin-Saint-Vincent-de-Paul, Université Paris-Descartes,8 Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, Paris,2 Service de Pharmacologie Médicale et Toxicologie, Hôpital Lapeyronie, CHU de Montpellier,3 Laboratoire de Bactériologie-Virologie, CHU de Montpellier, Hôpital Arnaud de Villeneuve, Montpellier,7 UMR 145, IRD, Centre de Recherche Cultures Santé Sociétés/IFEHA, Université Paul Cézanne, Aix en Provence, France,6 Service de Pédiatrie, CHU Sourô Sanou,4 Centre Muraz, Bobo Dioulasso, Burkina Faso5

Received 2 December 2008/ Returned for modification 14 March 2009/ Accepted 15 July 2009

We aimed in this study to describe efavirenz concentration-time courses in treatment-naïve children after once-daily administration to study the effects of age and body weight on efavirenz pharmacokinetics and to test relationships between doses, plasma concentrations, and efficacy. For this purpose, efavirenz concentrations in 48 children were measured after 2 weeks of didanosine-lamivudine-efavirenz treatment, and samples were available for 9/48 children between months 2 and 5 of treatment. Efavirenz concentrations in 200 plasma specimens were measured using a validated high-performance liquid chromatography method. A population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. The estimated minimal and maximal concentrations of efavirenz in plasma (Cmin and Cmax, respectively) and the area under the concentration-time curve (AUC) were correlated to the decrease in human immunodeficiency virus type 1 RNA levels after 3 months of treatment. The threshold Cmin (and AUC) that improved efficacy was determined. The target minimal concentration of 4 mg/liter was considered for toxicity. An optimized dosing schedule that would place the highest percentage of children in the interval of effective and nontoxic concentrations was simulated. The pharmacokinetics of efavirenz was best described by a one-compartment model with first-order absorption and elimination. The mean apparent clearance and volume of distribution for efavirenz were 0.211 liter/h/kg and 4.48 liters/kg, respectively. Clearance decreased significantly with age. When the recommended doses were given to 46 of the 48 children, 19% (44% of children weighing less than 15 kg) had Cmins below 1 mg/liter. A significantly higher percentage of children with Cmins of >1.1 mg/liter or AUCs of >51 mg/liter·h than of children with lower values had viral load decreases greater than 2 log10 copies/ml after 3 months of treatment. Therefore, to optimize the percentage of children with Cmins between 1.1 and 4 mg/liter, children should receive the following once-daily efavirenz doses: 25 mg/kg of body weight from 2 to 6 years, 15 mg/kg from 6 to 10 years, and 10 mg/kg from 10 to 15 years. These assumptions should be prospectively confirmed.

* Corresponding author. Mailing address: Unité de Recherche Clinique, Hôpital Tarnier, 89 rue d'Assas, 75006 Paris, France. Phone: 33158412884. Fax: 33158411183. E-mail: deborah.hirt{at}univ-paris5.fr

{triangledown} Published ahead of print on 27 July 2009.

{ddagger} This is an ANRS 12103 study.

Antimicrobial Agents and Chemotherapy, October 2009, p. 4407-4413, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.01594-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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