The U.S. FDA recently expanded the indication for efavirenz (EFV) to include children at least three months old based on a population pharmacokinetic (PK) model to assess dosing for this age group.1 These data were presented at the 14th International Pharmacokinetics Workshop.2
The recommended dose of efavirenz (EFV) for children and adolescents three years and above is based on body weight and ranges from 200 mg once daily for those weighing 10 to <15 kg, to 600 mg for those >40 kg. Prior to the FDA update, EFV was not recommended for children <3 years or <10 kg (this is still the case in the EU).
The population PK model was based on 3289 concentration values from 168 babies, children and adolescents, aged 3 months to 21 years (57 < 3 years), weighing 3.3 to 117 kg (from studies PACTG382, PACTG1021 and A1266922). The model also incorporated 1232 values from 24 healthy adults (A1266059). Paediatric trials contributed 88% of participants and 73% of observations for analysis. The model included pre-specified covariates: age, weight, gender and race.
Simulations of steady state EFV exposures (n=1000 PK parameter sets, 100 paediatric participants per weight category) were performed for various doses of EFV capsule-sprinkle and capsule formulations, in order to identify those that gave comparable exposure between participants weighing <10 kg and >10 kg. The criteria used for this were target steady state AUC 190-380 um*h and Cmax and Cmin of 5.2-8.2 and 1.9-2.9 ug/mL, respectively (80-125% of the reference Cmax and Cmin values from children weighing 10-15 kg).
The investigators found the steady state PK were well described by a linear two-compartment model with first-order absorption. Weight was a clinically meaningful covariate on EFV clearance, central volume and rate of absorption. Age was not significant in the presence of weight.
Simulation results suggested that the doses in table 1 produce comparable exposure to that of children >10 kg who received the current approved dose. These doses produced a median AUC within the target range; simulation results for Cmax and Cmin also supported them.
|Table 1: EFV Doses According to Weight Bands|
|Weight Band||Dose (mg Once Daily)|
|> 2.5 to <5 kg||100 mg|
|> 5 to <7.5 kg||150 mg|
|> 7.5 to 10 kg||200 mg|
The simulation results also confirm the current once daily dosing recommendation for children weighing >10 kg (>3 years).
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