Sînziana Cristea (1), Elke H.J. Krekels (1), Karel Allegaert (3,4), Amin Rostami-Hodjegan (5,6), Catherijne A.J. Knibbe (1,2)
(1) Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; (2) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands; (3) Intensive Care and Department of Pediatric Surgery, Erasmus MC - Sophia Children’s Hospital, Rotterdam, The Netherlands; (4) Department of Development and Regeneration, KU Leuven, Belgium; (5) Simcyp (A Certara Company), Blades Enterprise Centre, Sheffield, UK; (6) Manchester Pharmacy School, Manchester University, Manchester,UK
Objectives: Glomerular filtration (GF) has a key role in the renal elimination of many drugs. Establishing an accurate ontogeny function for this route is necessary to guide paediatric dosing regimens of drugs eliminated through GF. Here, the performances of published functions describing the maturation of GF rate (GFR) [2-6] are compared to observed values in the paediatric population[1].
Methods: The published GFR functions were either based on compounds from which ‘true’ GFR was derived (i.e. Cr-EDTA, inulin, mannitol[2-4],[6]) or on clearance estimations of drugs mainly excreted by GFR (i.e. aminoglycosides[5]). These functions relied on a single demographic characteristic (i.e. bodyweight [2,5] or body surface area [3]) or on a combination of characteristics (i.e. bodyweight with postmenstrual age [4,6]) to describe the GFR maturation profile. A paediatric population of 3200 individuals between the ages of 2.5 weeks and 20 years was simulated using Simcyp v13. The obtained demographic characteristics were then used to predict GFR with the published functions. The comparison between GFR predictions [2-6] and observations [1] was performed at two levels: qualitatively, based on visual comparison of GFR predictions and quantitatively, based on % prediction error (PE%) with an acceptance range of ±50%.
Results: All the five published functions were found to describe similar maturation patterns, within an acceptable PE% range throughout the entire age-range (absolute PE%: 17%-36%). However, for all functions, there was a tendency towards underprediction of GFR below the age of 5 years. The closer the predictions were to the adult value, the higher the prediction accuracy. When compared to the observed data, the function by Hayton[2] had the lowest PE% whereas the function from De Cock[5] had the highest PE%. Rhodin[4] and Salem[6] had overall similar absolute PE% values (22.5% vs 24%) and also when stratified per age range (
Conclusions: The GFR maturation functions based on data from compounds that measure ‘true’ GFR have an overall better performance than the one based on drug clearance. All functions underpredict GFR below the age of one year.
References:
[1] M. I. Rubin, E. Bruck, M. Rapoport, M. Snively, H. McKay, and a Baumler, “Maturation of Renal Function in Childhood: Clearance Studies.,” J. Clin. Invest., vol. 28, no. 5 Pt 2, pp. 1144–62, 1949.
[2] W. L. Hayton, “Maturation and growth of renal function: dosing renally cleared drugs in children.,” AAPS PharmSci, vol. 2, no. 1, p. E3, 2000.
[3] T. N. Johnson, A. Rostami-Hodjegan, and G. T. Tucker, “Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children,” Clin. Pharmacokinet., vol. 45, no. 9, pp. 931–956, 2006.
[4] M. M. Rhodin, B. J. Anderson, a. M. Peters, M. G. Coulthard, B. Wilkins, M. Cole, E. Chatelut, A. Grubb, G. J. Veal, M. J. Keir, and N. H. G. Holford, “Human renal function maturation: A quantitative description using weight and postmenstrual age,” Pediatr. Nephrol., vol. 24, no. 1, pp. 67–76, 2009.
[5] R. F. W. De Cock, K. Allegaert, J. M. Brussee, C. M. T. Sherwin, H. Mulla, M. De Hoog, J. N. Van Den Anker, M. Danhof, and C. a J. Knibbe, “Simultaneous pharmacokinetic modeling of gentamicin, tobramycin and vancomycin clearance from neonates to adults: Towards a semi-physiological function for maturation in glomerular filtration,” Pharm. Res., vol. 31, no. 10, pp. 2643–2654, 2014.
[6] F. Salem, T. N. Johnson, K. Abduljalil, G. T. Tucker, and A. Rostami-Hodjegan, “A re-evaluation and validation of ontogeny functions for cytochrome P450 1A2 and 3A4 based on in vivo data,” Clin. Pharmacokinet., vol. 53, no. 7, pp. 625–636, 2014.
Reference: PAGE 25 (2016) Abstr 5939 [www.page-meeting.org/?abstract=5939]
Poster: Drug/Disease modeling - Paediatrics