Simultaneous pharmacokinetic modeling of gentamicin, tobramycin and vancomycin clearance from neonates to adults: towards a semi-physiological function for maturation in glomerular filtration.
Roosmarijn F.W. De Cock1, Karel Allegaert2, Janneke M. Brussee1, Catherine M.T. Sherwin3, Hussain Mulla4, Matthijs de Hoog5, Johannes N. van den Anker5,6, Meindert Danhof1, Catherijne A.J. Knibbe1,7
(1) Division of Pharmacology, LACDR, Leiden University, Leiden, the Netherlands, (2) Neonatal Intensive Care Unit, University Hospital Leuven, Leuven, Belgium, (3) Division of Clinical Pharmacology & Clinical Trials Office Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA, (4) Department of Pharmacy, University Hospitals of Leicester, England, (5) Department of Pediatric Intensive Care, Erasmus MC - Sophia Children’s Hospital, Rotterdam, The Netherlands, (6) Division of Pediatric Clinical Pharmacology, Children’s National Medical Center, Washington, DC, USA, (7) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
Objectives: Since glomerular filtration rate (GFR) is responsible for the elimination of a large number of water-soluble drugs [1], the aim of this study was to develop a semi-physiological function for GFR maturation from neonates to adults.
Methods: In the pharmacokinetic analysis (NONMEM VI) based on data of gentamicin, tobramycin and vancomycin collected in 1760 patients (age 1 day-18 years, bodyweight 415g-85kg), a distinction was made between drug-specific and system-specific information. Since the maturational model for clearance is considered to contain system-specific information on the developmental changes in GFR [2], one GFR maturational function was derived for all three drugs.
Results: Simultaneous analysis of these three drugs showed that maturation of GFR mediated clearance from preterm neonates to adults was best described by a bodyweight-dependent exponent (BDE) function with an exponent varying from 1.4 in neonates to 1.0 in adults (ClGFR= Cldrug*(BW/4kg)BDE with BDE=2.23*BW-0.065). Population clearance values (Cldrug) for gentamicin, tobramycin and vancomycin were 0.21L/h, 0.28L/h and 0.39L/h for a full term neonate of 4kg, respectively.
Conclusions: Based on an integrated analysis of gentamicin, tobramycin and vancomycin, a semi-physiological function for GFR mediated clearance was derived that can potentially be used to establish evidence based dosing regimens of renally excreted drugs in children.
References:
[1] Alcorn J, McNamara PJ. Ontogeny of hepatic and renal systemic clearance pathways in infants: part I. Clin Pharmacokinet. 2002;41(12):959-98.
[2] Knibbe CA, Krekels EH, Danhof M. Advances in paediatric pharmacokinetics. Expert Opin Drug Metab Toxicol. 2011 Jan;7(1):1-8.
