Predicting glomerular filtration rate using clearance of amikacin
R.F.W. De Cock1, M. Danhof1, K. Allegaert2, M. de Hoog3, C.A.J. Knibbe1,3,4
(1) Division of Pharmacology, LACDR, Leiden University, Leiden, the Netherlands; (2) Neonatal Intensive Care Unit, University Hospital Leuven, Leuven, Belgium; (3) Department of Pediatric Intensive Care, Erasmus MC - Sophia Children’s Hospital, Rotterdam, the Netherlands; (4) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands
Objectives: Throughout childhood many physiological changes occur. In addition, renal function is influenced by physiological changes resulting in differences in glomerular filtration rate (GFR) and tubular secretion/absorption processes at different stages of development. However exact quantification of the renal function to predict the clearance of drugs eliminated by the renal route is lacking. The aim of this study is therefore to describe the population pharmacokinetics (PK) of amikacin, an antibiotic which is almost entirely eliminated by the kidney, in order to quantify age-related developmental changes in glomerular filtration rate (GFR) (1) in neonates.
Methods: The population PK analysis was performed using the non-linear mixed effects modeling software NONMEM version 6.2. in 715 neonates (postmenstrual age 24-43 weeks, postnatal age 1-30 days) (2). The influence of the following covariates was investigated: birth and current weight, postmenstrual (PMA), postnatal (PNA), and gestational age (GA), creatinaemia, coadminstration of ibuprofen and dopamine, growth restriction, positive blood culture, mechanical ventilation and prenatal exposure to betamethasone.
Results: A one compartment model best described the data. Birth weight was identified as the most important covariate for clearance. Additionally, PNA was identified as a second covariate for clearance, thereby quantifying maturation after birth. The predictive value of PMA proved to be limited in the studied population with a large variation in gestational age and postnatal age, because this measure does not distinguish between pre-natal and post-natal maturation. Current weight was found to be the most important covariate for volume of distribution.
Conclusions: Variability in amikacin clearance in neonates can be partly explained by birth weight and postnatal age, indicating that birth itself has an impact on magnitude and maturation of renal clearance. To further identify and quantify the influence of these covariates on the glomerular filtration rate, the study will be extended to older age ranges (extrapolation study) and other drugs like netilmicin, tobramycin, gentamycin and vancomycin (cross validation study). By using the maturation rates of clearance values of all these different drugs, it is anticipated to describe the influence of maturation on GFR and finally develop a maturational model for GFR throughout pediatric life until adults.
References:
[1]. Koren G, James A, Perlman M. A simple method for the estimation of glomerular filtration rate by gentamicin pharmacokinetics during routine drug monitoring in the newborn. Clin Pharmacol Ther1985 Dec;38(6):680-5.
[2]. Allegaert K, Scheers I, Cossey V, Anderson BJ. Covariates of amikacin clearance in neonates: the impact of postnatal age on predictability. Drug Metab Lett2008 Dec;2(4):286-9.
