Is the recommended dose of efavirenz optimal in young West African human immunodeficiency virus-infected children ?

2009

Article référencé dans le Web of Science WOS:000270020600049

Hirt D., Urien S., Olivier M., Peyrière H., Nacro B., Diagbouga S., Zoure E., Rouet F., Hien H., Msellati Philippe, Van de Perre P., Tréluyer J. M.

Antimicrobial Agents and Chemotherapy, 2009, 53 (10), 4407-4413 ISSN 0066-4804

We aimed in this study to describe efavirenz concentration-time courses in treatment-naive 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 (C-min and C-max, 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 C-min (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 C(min)s below 1 mg/liter. A significantly higher percentage of children with C(min)s 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 log(10) copies/ml after 3 months of treatment. Therefore, to optimize the percentage of children with C(min)s 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.

Entomologie médicale / Parasitologie / Virologie [052]

AFRIQUE DE L'OUEST

Fonds IRD [F B010089805]

PAR00004148