Renal Drug Clearance in Preterm Neonates: Relation to Prenatal Growth

Abstract

Aminoglycosides and glycopeptides are almost exclusively eliminated by renal excretion. 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 investigated whether prenatal growth also affects clearance of drugs such as aminoglycosides or glycopeptides that are eliminated through the kidney. Observations collected in two population pharmacokinetic studies involving preterm neonates and 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. Data from 1212 drug measurements (vancomycin, 648; amikacin, 564) in 531 subjects (vancomycin, 249; amikacin, 282) were available for study. Neonates born small for gestational age (SGA) were found to have a 16.2% (coefficient of variation, 12.2%) reduction in drug clearance. This effect was present from birth up to the postnatal age of 4 weeks. The covariate size (weight 0.75) explained 47.3% of drug clearance; PMA, 25.2%; coadministration of a nonselective cyclo-oxygenase inhibitor, 3.5%; renal function, 7.6%; and SGA, 1.7%. Renal drug clearance is significantly lower in preterm neonates born SGA than in appropriate-for-gestational-age (AGA) controls. This reduced clearance was observed not only at birth but also up to the postnatal age of 4 weeks.

Impact of Gestational Age and Birth Weight on Amikacin Clearance on Day 1 of Life

“…In contrast, neonates with IUGR have been shown to eliminate vancomycin more slowly in the first 4 wk of life (20,31). Because vancomycin elimination is largely through the kidney, these studies are consistent with the influence of birth weight z score on the clearance of amikacin in our study.…”

“…(34) did find more individuals with an impaired GFR (Ͻ90 ml/min per 1.73 m 2 ) in the IUGR group. We found a positive correlation between amikacin clearance and GA, as has been described for aminoglycosides (18,20,(35)(36)(37)(38)(39). The absolute value of amikacin clearance (0.61 ml/kg per min) is comparable to previously reported values (0.52 to 0.6 ml/kg per min (17)(18)(19)40).…”

“…Previously, the clearance of amikacin was used as a marker of GFR in neonates (17)(18)(19)(20) because aminoglycoside clearance correlates well with GFR (21). Amikacin is often used in neonates in whom perinatal infection is suspected, and amikacin levels are routinely monitored.…”

Pharmacokinetics in neonatal prescribing: evidence base, paradigms and the future

“…Premature neonates have a slower rate of kidney development [61] and smaller kidney volume [62] although the administration of betamethasone has positive effects on kidney development [63]. Babies who are born small for gestational age have been shown to have lower renal excretion than appropriate for gestational age counterparts [64]. Creatinine at birth is not a reliable marker of glomerular filtration rate and largely reflects maternal renal function for the first few hours.…”

Pharmacokinetic Variability of Amikacin After Once-Daily and Twice-Daily Dosing Regimen in Full-Term Neonates

“…However, in these studies, pre-and full-term neonates were included (10,18,30). There were as well conflicting data if postmenstrual (sum of gestational and neonatal) age was a good predictor of aminoglycoside CL (12,17,23,31). Considering the fact that the major changes in blood flow occur during the transition from the intrauterine to the extrauterine environment, it seems rational to observe gestational and neonatal age as independent factors since their influences on amikacin CL are different due to distinct causes (32,33).…”