Neonatal Population Pharmacokinetics of Phénobarbital Derived from Routine Clinical Data

Abstract

Routine clinical pharmacokinetic (PK) data collected from 59 preterm infants who received phénobarbital were analyzed to estimate population PK parameters. Birth weights ranged from 600 to 3,620 g (mean 1,520 g), and gestational ages ranged from 24 to 42 weeks (mean 31 weeks). Data were analyzed using NONMEM, a computer program designed for population PK analysis. The mean (±CV) clearance of phénobarbital was 0.0047 liter/h/kg (± 19%) and the mean (±CV) volume of distribution (Vd) was 0.96 liter/kg (± 16%). The calculated mean serum half-life was 141 h. Clearance was not affected by gestational age, sex, asphyxia, or duration of therapy. Vd was not affected by gestational age or sex but was increased by 13% in the presence of asphyxia (5-min Apgar score <5, p < 0.05).

Paediatric pharmacokinetics: key considerations

“…This technique was first introduced into paediatric clinical pharmacology in the mid-1980s [85], and has remained popular owing to the ability to analyze studies with sparse and unbalanced pharmacokinetic data, typical of paediatric trials with ethical and logistical constraints. Regulatory guidance now recommends this approach for paediatric pharmacokinetic studies [86,87].…”

Comparison of nonparametric methods in nonlinear mixed effects models

“…Simulation 1 was inspired by the phenobarbital PK analysis of Grasela & Donn (1985). The PK of phenobarbital after intravenous administration is described with a one compartment model with first order elimination, as follows: for j = 1..n i ,…”

“…In order to choose the values of θ * and of the first moments of X i , we analyzed the real dataset (Grasela & Donn, 1985), without taking into account the covariates and assuming that X i is log-normal. The estimation was performed using NONMEM software (subroutine ADVAN1 TRANS2, method FOCEI).…”

“…The values of modes and proportions were arbitrary chosen in such a way that the overall mean and variance were similar to those estimated from the real dataset used by Grasela & Donn (1985). Figure 1.…”

“…The value of D was set to the mean of the initial doses of the real dataset used by Grasela & Donn (1985): D = 25.7µg. We simulated some rich and some sparse datasets.…”