Quantification of renal drug clearance in neonates born Small for Gestational Age (SGA) compared to neonates born Appropriate for Gestational Age (AGA)
Anne van Rongen (1), Nicole ter Laak (1), Pheline X.M. Remijn (1), Elke H.J. Krekels (1), Swantje Völler (1), Karel Allegaert (2,3,4), Anne Smits (2,5), Elisabet I. Nielsen (6), Catherine M.T. Sherwin (7), Michiel F. Schreuder (8), Robert B. Flint (4,9), Sinno H.P. Simons (9), Catherijne A.J. Knibbe (1,10)
(1) Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; (2) Department of Development and Regeneration, KU Leuven, Leuven, Belgium; (3) Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; (4) Department of Hospital Pharmacy, Erasmus MC, Rotterdam, The Netherlands; (5) Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium; (6) Department of Pharmacy, Uppsala University, Sweden; (7) Department of Pediatrics, Wright State University Boonshoft School of Medicine, Dayton Children’s Hospital, Dayton, Ohio, United States; (8) Department of Pediatric Nephrology, Radboudumc Amalia Children’s Hospital, Nijmegen, The Netherlands; (9) Dept. of Pediatrics, Division of Neonatology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands; (10) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
Objectives: The pharmacokinetics of drugs in the heterogeneous group of preterm and term neonates is known to vary largely as a result of variation in for instance gestational age (GA), birth bodyweight (bBW) and postnatal age (PNA). Previous efforts have focused on quantifying the influence of these covariates, with a combination of bBW or GA and PNA often being stronger covariates than postmenstrual age (PMA, i.e. GA+PNA) [1,2]. In these studies, so far, no specific attention has been paid to neonates that are born small for gestational age (SGA), i.e. with a bBW less than the 10th percentile of the bBW for their GA, as compared to appropriate for gestational age (AGA) counterparts. The aim of this study is to determine the influence of being born SGA on the clearance (CL) and volume of distribution (Vd) of gentamicin and amikacin in neonates.
Methods: For both gentamicin and amikacin datasets [3-8], we used the previously published two compartment model with equalized central and peripheral volumes [1,10]. For gentamicin, 733 (pre)term neonates with a median (range) GA of 35 (23-42) weeks, PNA of 3 (1-30) days, bBW of 2390 (440-5240) g and current bodyweight (cBW) of 2385 (440-5420) g were available [3,4]. For amikacin, 944 (pre)term neonates with a GA of 32 (24-42) weeks, PNA of 3 (1-30) days, bBW of 1780 (420-5420) g and cBW of 1920 (420-5420) g were available. Using the Fenton growth charts, 84 (11.5%) and 121 (12.8%) neonates were identified as SGA in these datasets, respectively [9]. Zscores of bBW for GA were calculated with a Zscore of 0.11 (-4.1-4.8) for gentamicin and -0.17 (-3.4-4.0) for amikacin [9]. A covariate analysis was performed in which the influence of SGA and Zscore were tested in addition to bBW or GA as antenatal predictor and PNA as postnatal predictor for CL and cBW on Vd [1,10] using NONMEM 7.4.
Results: Visual inspection of the variation in gentamicin and amikacin CL of the final published model [1,10] versus bBW showed a trend towards higher CL for SGA compared to AGA neonates. When these CL values were plotted against GA, SGA neonates showed lower CL values. After including SGA in the covariate model in addition to bBW and PNA, CL proved 19% higher in SGA neonates compared to AGA neonates for both gentamicin (ΔOFV -16.0) and amikacin (ΔOFV -19.5). When SGA was added as covariate in the GA and PNA model, gentamicin and amikacin CL was significantly decreased with 30% (ΔOFV -64.6) and 32% (ΔOFV -88.2), respectively, for SGA compared to AGA neonates. Overall, the bBW and PNA + SGA model described the data significantly better than the GA and PNA + SGA model for both gentamicin (OFV 2258.4 vs 2316.4) and amikacin CL (OFV 4679.3 vs 4744.4). SGA was not a covariate for Vd for either drug.
Conclusions: For a neonatal covariate model for gentamicin or amikacin with bBW and PNA as covariates [1,10], CL for SGA neonates is 19% underestimated, potentially because the maturation for SGA neonates is further developed than predicted by their bBW. In case GA is used as covariate instead of bBW, CL for SGA neonates is 30% overestimated, probably because the maturation for SGA neonates is behind as predicted by their GA. These results imply that SGA should be considered when designing dosing guidelines for renally cleared drugs in neonates.
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