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Pharmacokinetics of zidovudine in infants: a population analysis across studies
M Mirochnick1, E Capparelli, J Connor
1Department of Pediatrics, Boston Medical Center and Boston University School of Medicine, Mass 02118, USA.
Insights
Zidovudine elimination speeds up in infants after birth, maturing faster in term infants than preterm ones. Higher bioavailability was noted in younger infants, suggesting developmental differences in drug metabolism.
Area of Science:
- Pharmacology
- Pediatrics
- Infectious Diseases
Background:
- Zidovudine is standard for HIV in newborns and infants.
- Developmental pharmacology of zidovudine in early life is not fully understood.
Purpose of the Study:
- To describe developmental pharmacology of zidovudine in newborns and infants.
- To estimate zidovudine pharmacokinetic parameters in infants.
Main Methods:
- Population pharmacokinetic analysis using NONMEM software.
- Utilized 698 serum samples from 83 infants (26-41.5 weeks gestational age).
- Examined factors influencing elimination rate, volume of distribution, and bioavailability.
Main Results:
- Zidovudine elimination matures rapidly in term infants within weeks, slower in preterm infants.
- Increased bioavailability observed in infants under 14 days old.
- No impact of gender, race, or co-exposure to didanosine/nevirapine on elimination.
Conclusions:
- Zidovudine elimination kinetics mature significantly in the first months of life.
- Maturation patterns differ between term and preterm infants.
- Higher bioavailability in younger infants linked to reduced first-pass metabolism.
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.