Age-related effects on nelfinavir – M8 pharmacokinetics – A population study in 182 children

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Objective: As a relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established, the large inter individual variability observed in children was analysed in order to optimise individual treatment schedule for this drug in a paediatric population.

Methods : A population pharmacokinetic model was developed in order to describe the concentration-time-course of nelfinavir and its active metabolite M8, in children. Individual characteristics, such as age or bodysize, that may influence the nelfinavir-M8 pharmacokinetics were investigated. Data from therapeutic drug monitoring in 182 children, aged from 3 days to 17 years, treated with nelfinavir were retrospectively analysed with the NONMEM program. Then FDA current recommendations were evaluated in 3 age groups : from 2 to 13 years, from 2 months to 2 years and younger than 2 months with twice- or thrice-daily regimens, estimating the percentage of children who reach the target minimum plasma concentration (0.8 mg/L), using Bayesian estimates.

Results: Nelfinavir pharmacokinetics was described by a one compartment model with linear absorption and elimination and M8 produced from the nelfinavir central compartment. Pharmacokinetic estimates and the corresponding inter-subject variabilities (%) for the model were: nelfinavir total clearance 0.92 L/h/kg (39%), volume of distribution 7.3 L/kg (112%), absorption rate 0.5 h^-1 , formation clearance fraction to M8 0.025 and M8 elimination rate 1.86 h^-1 (49%). Nelfinavir total clearance and volume of distribution decreased as a function of age. M8 elimination rate was increased by concomitant administration of nevirapine or efavirenz. A higher percentage of children had minimum plasma concentration above 0.8 mg/L with the thrice daily regimen than with the twice-daily regimen recommended by the FDA (especially in young groups). Our data confirm that the FDA recommendations i.e. 25 to 35 mg/Kg TID or 50 to 60 mg/Kg BID for children from 2 to 13 years, 40 to 50 mg/kg TID or 60 to 75 mg/kg BID for children from 2 months to 2 years are optimal. However in children younger than 2 months, the proposed nelfinavir newborn’s dose of 40 mg/Kg BID is inadequate and we suggest to increase the dose to 50 to 60 mg/Kg administered thrice daily. This assumption should be further evaluated.