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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Is the recommended dose of efavirenz optimal in young West African human immunodeficiency virus-infected children?
Antimicrobial Agents and Chemotherapy, Volume 53, No. 10, Year 2009
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Description
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. Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Authors & Co-Authors
Hirt, Déborah
France, Paris
Hopital Cochin Ap-hp
France, Paris
Hôpital Tarnier
Urien, Saík
France, Paris
Hopital Cochin Ap-hp
France, Paris
Hôpital Tarnier
Olivier, Mathieu
France, Montpellier
Hopital Lapeyronie
Peyrière, Hélène
France, Montpellier
Hopital Lapeyronie
Nacro, Boubacar
Burkina Faso
Chu Souro Sanou
Diagbouga, Serge P.
Burkina Faso, Ouagadougou
Centre Muraz
Zouré, Emmanuelle
Burkina Faso
Chu Souro Sanou
Burkina Faso, Ouagadougou
Centre Muraz
Rouet, François
France, Marseille
Aix Marseille Université
Burkina Faso, Ouagadougou
Centre Muraz
Hien, Hervé M.
France, Marseille
Aix Marseille Université
Burkina Faso, Ouagadougou
Centre Muraz
Msellati, Philippe
France, Marseille
Aix Marseille Université
van de Perre, Philippe
France, Montpellier
Hopital Arnaud de Villeneuve
Tréluyer, Jean Marc
France, Paris
Hopital Cochin Ap-hp
France, Paris
Hôpital Tarnier
Statistics
Citations: 47
Authors: 12
Affiliations: 7
Identifiers
Doi:
10.1128/AAC.01594-08
ISSN:
00664804
e-ISSN:
10986596
Research Areas
Maternal And Child Health
Study Design
Cross Sectional Study