Bayesian parameter estimates of nelfinavir and its active metabolite, hydroxy-tert-butylamide, in infants perinatally infected with human immunodeficiency virus type 1

Abstract

The objective of the present study was to develop a population pharmacokinetic model for nelfinavir mesylate (NFV) and nelfinavir hydroxy-tert-butylamide (M8), the most abundant metabolite of NFV, in infants vertically infected with human immunodeficiency virus type 1 and participating in the Paediatric European Network for Treatment of AIDS 7 study. Plasma NFV concentrations were determined during repeated NFV administrations (two to three times a day). Eighteen infants younger that age 2 years participated in this study. The doses administered ranged from 71 to 203 mg/kg of body weight/day. Pharmacokinetic parameter estimates were obtained by a compartmental approach by using a kinetic model to simultaneously fit NFV and M8 (active metabolite) concentrations. M8 was shown to be formation rate limited and was characterized by first-order rate constants of formation and elimination. Body weight was found to be a more appropriate predictor than age of the changes in (i) the rate of metabolism, (ii) the elimination rate constant of NFV, and (iii) NFV clearance. Population parameters were computed to account for the relationship between the rate of metabolism and body weight. The estimated NFV and M8 elimination half-lives were 4.3 and 2.04 h, respectively. The estimated NFV clearance was 2.13 liters/h/kg. The M8 concentration-to-NFV concentration ratio was 0.64 +/- 0.44. In conclusion, the population pharmacokinetic model describing the dispositions of NFV and M8 should facilitate the design of future studies to elucidate the relative contributions of the parent compound and M8 to the pharmacological and toxic effects of NFV therapy.

FIG. 1.

Structural model used to fit NFV and M8 data. GI, gastrointestinal tract; 1 and 2, compartments of distribution; k_a, first-order input rate; k₁₂, first-order rate of metabolism; k₁₀ and k₂₀, first-order elimination rate constants; V₁ and V₂, estimated parameters defining the volumes of distribution of the two compartments, respectively.

FIG. 2.

Relationships between patient body weight and NFV CL/F and between patient body weight and k₁₂.

FIG. 3.

Model performance. (A) Model-predicted versus observed NFV concentrations based on population parameter estimates; (B) predicted NFV concentrations based on population parameter estimates versus time; (C) weighted residuals versus predicted NFV concentrations based on population parameter estimates. The dotted line represents the line of identity. The solid line represents the zero abscissa line.

FIG. 4.

Model performance. (A) Model-predicted versus observed M8 concentrations based on population parameter estimates; (B) predicted M8 concentrations based on population parameter estimates versus time; and (C) weighted residuals versus predicted M8 concentrations based on population parameter estimates. The dotted line represents the line of identity. The solid line represents the zero abscissa line.

FIG. 5.

Typical posterior individual fittings for a patient aged 6 months receiving NFV BID. (A) NFV; (B) M8. The open symbols represent the individual predicted plasma concentrations, and the filled symbols are the observed plasma concentrations.

FIG. 6.

Simulation for a typical patient. Heavy lines, population fitted model; thin lines, 95% confidence interval. The dose administered was 500 mg BID.