Background: No single study of ZDV pk in infants contains the range of patients needed to fully describe the impact of demographic factors, developmental changes, or administration of concomitant medications on ZDV pk parameters.

Methods: We performed a population pk analysis using NONMEM of patients who had enrolled in five pediatric ACTG protocols or were premature infants who had ZDV concentrations drawn for therapeutic drug monitoring. The patient population included 83 infants studied with 698 serum samples around 153 doses (58 IV, 77 enteral, 18 transplacental washout). Mean gestational age at birth was 37.5 weeks (range: 26 weeks to term), mean postnatal age at initial sampling was 12.2 days (range: newborn to 5 months), mean weight at initial sampling was 3.1 kg (range: 0.71 to 6.0 kg), gender was 37 female/44 male/2 unknown, ethnicity was 42 black/14 hispanic/15 white/12 unknown.

Results: The data best fit a two compartment open model. The influences of demographic and clinical factors on the elimination rate constant (K), volume of distribution (Vd) and bioavailability (F1) were evaluated. Gender, race, and exposure to ddI or nevirapine had no impact on ZDV elimination. ZDV elimination was slow immediately after birth, but increased rapidly in full term infants over the first weeks of life, reaching a plateau by around 4 weeks of age, as described by the function: K = 0.113 +(1.03*PNA)/(13.3+PNA), where PNA = postnatal age. In infants less than 35 weeks gestational age, ZDV elimination was slower immediately after birth and increased at a reduced rate as compared to the term infants, and was described by: K = 0.0956 + (0.00832*PNA). Average F1 was increased in infants less than 14 days old, consistent with decreased first-pass metabolism associated with reduced hepatic clearance.

Conclusions: ZDV elimination kinetics undergo large developmental changes in infancy, and the pattern of maturation differs in term and preterm infants. In adults, glucuronidation is the main route of ZDV metabolism. Maturation of ZDV clearance in infants appears to parallel that of bilirubin. This analysis demonstrates how data from multiple studies can be pooled and analyzed with population pk techniques to address questions that can not be answered using the data from individual studies and traditional pk techniques.