Does growth restriction at birth contribute to the interindividual variability of renal drug clearance in the first month of life?

Abstract

Background: Aminoglycosides and glycopeptides are almost exclusively eliminated by renal route. Postmenstrual age (PMA) is the best predictor of their clearance, presumably because it predicts the time course of development of the glomerular filtration rate (GFR). Intrauterine growth restriction has an impact on the normalized weight of the kidney, on the number of nephrons, on GFR and on tubular function in human perinatal life. We therefore investigated whether prenatal growth also effects clearance of drugs such as aminoglycosides or glycopeptides that are eliminated through the renal system. Methods: Observations collected in two population pharmacokinetic studies in preterm neonates investigating amikacin and vancomycin in the first month of postnatal life were used to estimate the impact of prenatal growth (as judged by birth weight for gestational age) on the clearance of these drugs (ref 1,2) Results: Data from 1212 drug assay samples (vancomycin 648, amikacin 564) in 531 subjects (vancomycin 249, amikacin 282) were available. Neonates born small for gestational age (SGA) were found to have a 16,2% (CV 12,2%) reduction in drug clearance. This effect was present from birth up to the postnatal age of 4 weeks. The covariates size (weight 0,75) explained 47,3%, PMA 25,2%, co-administration of a non-selective cyclo-oxygenase inhibitor 3,5%, renal function 7,6% and SGA 1,7% of drug clearance. Conclusions: Renal drug clearance is significantly lower in preterm neonates born SGA compared to controls born appropriate-for-gestational age (AGA). This reduced clearance was not only observed at birth, but was also documented up to the postnatal age of 4 weeks.