Age-related effects on nelfinavir and M8 pharmacokinetics: a population study with 182 children

Abstract

As a relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established, nelfinavir pharmacokinetics was investigated in order to optimize the individual treatment schedule in a pediatric population. A population pharmacokinetic model was developed to describe the concentration-time course of nelfinavir and its active metabolite M8. Individual characteristics were used to explain the large interindividual variability in children. Data from therapeutic drug monitoring in 182 children treated with nelfinavir were analyzed with NONMEM. Then Food and Drug Administration (FDA) current recommendations were evaluated estimating the percentage of children who reached the target minimum plasma concentration (0.8 mg/liter) by using Bayesian estimates. Nelfinavir pharmacokinetics was described by a one- compartment model with linear absorption and elimination. Pharmacokinetic estimates and the corresponding intersubject variabilities for the model were as follows: nelfinavir total clearance, 0.93 liters/h/kg (39%); volume of distribution, 6.9 liters/kg (109%); absorption rate, 0.5 h(-1); formation clearance fraction to hydroxy-tert-butylamide (M8), 0.025; M8 elimination rate, 1.88 h(-1) (49%). Apparent 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. Our data confirm that the FDA recommendations for children from 2 to 13 years are optimal and that the dose recommended for children younger than 2 years is adequate for the children from 2 months to 2 years old. However, in children younger than 2 months, the proposed nelfinavir newborn dose of 40 mg/kg of body weight twice daily is inadequate and we suggest increasing the dose to 50 to 60 mg/kg administered thrice daily. This assumption should be further evaluated.

FIG. 1.

Schematic representation of the pharmacokinetic compartment model for the simultaneous prediction of nelfinavir and plasma M8 concentration after nelfinavir oral administration. Nelfinavir (in compartment 1) underwent irreversible biotransformation into M8 (in compartment 2).

FIG. 2.

Graphic of distribution of sample collection times (frequency versus time after dose).

FIG. 3.

Changes in apparent elimination clearance of nelfinavir as a function of age. ○, Individual clearance estimates from the base model; —, clearance predicted by the model = 0.92 × (AGE/8.2)^−0.29.

FIG. 4.

Population predicted versus observed nelfinavir and plasma M8 concentrations from the final model. Solid line, identity line.

FIG. 5.

Percentage of the 121 children from 2 to 13 years with a minimum plasma concentration above 0.8 mg/liter as a function of daily dose and frequency of administration. Solid line, administration every 8 h; dotted line, administration every 12 h; vertical line, minimal FDA-recommended doses of 25 mg/kg TID (solid line) and 50 mg/kg BID (dotted line).

FIG. 6.

Percentage of the 36 children from 2 months to 2 years with a minimum plasma concentration above 0.8 mg/liter as a function of daily dose and frequency of administration. Solid line, administration every 8 h; dotted line, administration every 12 h; vertical line, minimal FDA-recommended doses of 40 mg/kg TID (solid line) and 60 mg/kg TID (dotted line).

FIG. 7.

Percentage of the 25 children younger than 2 months with a minimum plasma concentration above 0.8 mg/liter as a function of daily dose and frequency of administration. Solid line, administration every 8 h; dotted line, administration every 12 h; vertical dotted line, newborn's FDA-recommended dose of 40 mg/kg BID.