M Mirochnick1, E Capparelli, J Connor. 1. Department of Pediatrics, Boston Medical Center and Boston University School of Medicine, Mass 02118, USA.
Abstract
BACKGROUND: Although the use of zidovudine in newborns and infants has become standard therapy for prophylaxis and therapy of human immunodeficiency virus infection, the developmental pharmacology of zidovudine in the first months of life has not been fully described. METHODS: We used population analysis to estimate zidovudine pharmacokinetic parameters in newborns and infants who either participated in one of five Pediatric AIDS Clinical Trials Group (PACTG) protocols or were premature infants who had zidovudine concentrations drawn for therapeutic drug monitoring. The data set consisted of 698 serum samples from 83 infants with a mean gestational age at birth of 37.5 weeks (range, 26.0 to 41.5 weeks), mean postnatal age at sampling of 19.3 days (range, 0 to 144 days), and a mean weight at sampling of 3.1 kg (range, 0.71 to 6.0 kg). With use of the program NONMEM and a two-compartment open model, the influences of demographic and clinical factors on the elimination rate constant (k10), volume of distribution of the central compartment (Vc) and bioavailability (F1) were examined. RESULTS: Zidovudine elimination was slow immediately after birth but increased rapidly in term infants during the first weeks of life, reaching a plateau by 4 to 8 weeks of age. In premature infants, zidovudine elimination increased at a much slower rate than in the term infants. Gender, race, and exposure to didanosine or nevirapine had no impact on zidovudine elimination. Bioavailability was increased in infants less than 14 days old. CONCLUSIONS: Zidovudine elimination kinetics undergo large increases during the first months of life, and the pattern of maturation is different in term and preterm infants. Higher bioavailability in younger infants is consistent with decreased first-pass metabolism associated with reduced clearance.
BACKGROUND: Although the use of zidovudine in newborns and infants has become standard therapy for prophylaxis and therapy of human immunodeficiency virus infection, the developmental pharmacology of zidovudine in the first months of life has not been fully described. METHODS: We used population analysis to estimate zidovudine pharmacokinetic parameters in newborns and infants who either participated in one of five Pediatric AIDS Clinical Trials Group (PACTG) protocols or were premature infants who had zidovudine concentrations drawn for therapeutic drug monitoring. The data set consisted of 698 serum samples from 83 infants with a mean gestational age at birth of 37.5 weeks (range, 26.0 to 41.5 weeks), mean postnatal age at sampling of 19.3 days (range, 0 to 144 days), and a mean weight at sampling of 3.1 kg (range, 0.71 to 6.0 kg). With use of the program NONMEM and a two-compartment open model, the influences of demographic and clinical factors on the elimination rate constant (k10), volume of distribution of the central compartment (Vc) and bioavailability (F1) were examined. RESULTS:Zidovudine elimination was slow immediately after birth but increased rapidly in term infants during the first weeks of life, reaching a plateau by 4 to 8 weeks of age. In premature infants, zidovudine elimination increased at a much slower rate than in the term infants. Gender, race, and exposure to didanosine or nevirapine had no impact on zidovudine elimination. Bioavailability was increased in infants less than 14 days old. CONCLUSIONS:Zidovudine elimination kinetics undergo large increases during the first months of life, and the pattern of maturation is different in term and preterm infants. Higher bioavailability in younger infants is consistent with decreased first-pass metabolism associated with reduced clearance.
Authors: Penelope A Demas; Mayris P Webber; Ellie E Schoenbaum; Jeremy Weedon; Janis McWayne; Elizabeth Enriquez; Mahrukh Bamji; Genevieve Lambert; Donald M Thea Journal: Pediatrics Date: 2002-09 Impact factor: 7.124