Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, October 2009, p. 4399-4406, Vol. 53, No. 10
0066-4804/09/$08.00+0 doi:10.1128/AAC.01187-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Didanosine Population Pharmacokinetics in West African Human Immunodeficiency Virus-Infected Children Administered Once-Daily Tablets in Relation to Efficacy after One Year of Treatment
,
Déborah Hirt,1,2*
Christophe Bardin,3
Serge Diagbouga,4
Boubacar Nacro,5
Hervé Hien,4
Emmanuelle Zoure,5
François Rouet,4
Adama Ouiminga,4
Saik Urien,1,2
Vincent Foulongne,6
Philippe Van De Perre,6
Jean-Marc Tréluyer,1,2,7 and
Philippe Msellati8
EA3620,1 Service de Pharmacologie Clinique, AP-HP, Hôpital Cochin-Saint-Vincent-de-Paul, Université Paris-Descartes,7 Unité de Recherche Clinique, AP-HP, Hôpital Tarnier,2 Service de Pharmacie-Pharmacologie-Toxicologie, AP-HP, Hôtel-Dieu, Paris,3 Université Montpellier 1, EA 4205, Transmission, Pathogenèse et Prévention de l'Infection par le VIH, and CHU Montpellier, Laboratoire de Bactériologie-Virologie, Montpellier,6 UMR 145, IRD, Université de Montpellier 1, Centre de Recherche Cultures Santé Sociétés/IFEHA, Université Paul Cézanne, Aix en Provence, France,8 Centre Muraz,4 Service de Pédiatrie, CHU Sourô Sanou, Bobo Dioulasso, Burkina Faso5
Received 6 September 2008/ Returned for modification 8 January 2009/ Accepted 25 June 2009
Our objective was to study didanosine pharmacokinetics in children after the administration of tablets, the only formulation available in Burkina Faso for which data are missing, and to establish relationships between doses, plasma drug concentrations, and treatment effects (efficacy/toxicity). Didanosine concentrations were measured for 40 children after 2 weeks and for 9 children after 2 to 5 months of treatment with a didanosine-lamivudine-efavirenz combination. A population pharmacokinetic model was developed with NONMEM. The link between the maximal concentration of the drug in plasma (Cmax), the area under the concentration-time curve (AUC), and the decrease in human immunodeficiency virus (HIV) type 1 RNA levels after 12 months of treatment was evaluated. The threshold AUC that improved efficacy was determined by the use of a Wilcoxon test for HIV RNA, and an optimized dosing schedule was simulated. Didanosine pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. The apparent clearance and volume of distribution were higher for tablets, probably due to a lower bioavailability with tablets than with pediatric powder. The decrease in the viral load after 12 months of treatment was significantly correlated with the didanosine AUC and Cmax (P 
0.02) during the first weeks of treatment. An AUC of >0.60 mg/liter·h was significantly linked to a greater decrease in the viral load (a decrease of 3 log10 versus 2.4 log10 copies/ml; P = 0.03) than that with a lower AUC. A didanosine dose of 360 mg/m2 administered as tablets should be a more appropriate dose than 240 mg/m2 to improve efficacy for these children. However, data on adverse events with this dosage are missing.
* 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
Published ahead of print on 6 July 2009.
This is an ANRS 12103 study.
Antimicrobial Agents and Chemotherapy, October 2009, p. 4399-4406, Vol. 53, No. 10
0066-4804/09/$08.00+0 doi:10.1128/AAC.01187-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Copyright © 2009 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»