Is the Recommended Dose of Efavirenz Optimal in Young West African Human Immunodeficiency Virus-Infected Children?

Abstract

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 (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 ⅐ 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.The combination of didanosine (ddI), lamivudine (3TC), and efavirenz (EFV) once daily has improved compliance for adults and shown good antiretroviral efficacy (12); moreover, the treatment could be better tolerated in the long term (5, 6, 13). For children, the efficacy and tolerance of this ddI-3TC-EFV combination have not been investigated. The aims of the BURKINAM (ANRS 12103) study, then, were to investigate the pharmacokinetics of EFV, ddI, and 3TC given once daily in children 30 months to 15 years old and to evaluate the efficacy and tolerance of this combination.EFV is metabolized exclusively via CYP2B6 (cytochrome P450 isoenzyme) in the liver (20). Several factors (covariates), such as age (9), duration of treatment (7), or ethnici...

Pharmacometric Characterization of Efavirenz Developmental Pharmacokinetics and Pharmacogenetics in HIV-Infected Children

“…The effect of age on EFV CL/F in children was recently investigated using a population pharmacokinetic analysis (41). The study demonstrated a decrease in CL/F by age in patients 2.8 to 14.7 years old.…”

Pharmacology and immuno-virologic efficacy of once-a-day HAART in African HIV-infected children: ANRS 12103 phase II trial

“…Despite the satisfactory pharmacokinetics of DDI, 3TC and EFV, 15,18 target DDI plasma concentrations were not always reached in some of the youngest children, probably because the pills were not enteric-coated. Dose adaptation of the three drugs for the youngest children (< 15-17 kg in weight) would probably improve efficacy.…”

“…A pharmacokinetic model was built for each drug. 15,18 For 3TC, a two-compartment model in which the slope of the distribution was assumed to be equal to the absorption rate constant adequately described the data, an allometric scaling was added.…”

Pharmacokinetics of Efavirenz at a High Dose of 25 Milligrams per Kilogram per Day in Children 2 to 3 Years Old

“…At the start of the trial, no EFV dosing recommendations for children less than 3 years old were available. Therefore, the EFV dosing regimen was selected through simulations based on the results of a trial conducted in Burkina Faso which recommended 25 mg/kg of body weight/day for all children 2 to 4 years of age (6).…”