POPULATION PHARMACOKINETICS OF PHENOBARBITAL IN NEWBORNS DETERMINED BY NONMEM ANALYSIS

Abstract

Routine clinical pharmacokinetic (PK) data from 59 newborns, gestational ages 24-42 weeks (mean ± SD = 31±4.1) and birthweights 600-3620 gm (mean ± SD = 1520±700) who received anticonvulsant doses of phenobarbital (PB) were evaluated using NONMEM analysis. Fifty of these infants were less than 1800 gm and were treated for one week to prevent cerebral hemorrhage. Infants initially received 20 mg/kg of PB IV followed by maintenance doses of 2.5 mg/kg every 12 hours. Serum PB was measured 2 hours after loading and on days 3 and 6.Mean serum PB concentration post-loading was 19.8 ± 3.7 (SD) μg/ml. The mean apparent volume of distribution (AVd) was 0.96±0.024 (SEM) L/kg with a coefficient of variation (CV) of 16%. Mean clearance was 0.08 ± 0.003 (SEM) ml/min/kg, with a CV of 19%. Calculated mean serum half-life was 140 hrs.Within this population, neither gestational age nor birthweight had an effect on PK parameters. Asphyxia (5 min Apgar score < 5), on the other hand, had an effect on AVd, with a 13.7% increase noted in asphyxiated versus non-asphyxiated infants, p < 0.05.We conclude: (1) NONMEM is an accurate and easily implemented method of population PK analysis in newborns, (2) inter-individual variability in AVd and clearance of PB is minimal in the first week of life, and (3) alterations in PK parameters of phenobarbital are seen in asphyxia, where increases in AVd may result in lower than expected serum concentrations.