S Cristea (1), EHJ Krekels (1), P De Cock (2, 3), P De Paepe (3), K Allegaert (4, 5), CAJ Knibbe (1,6)
(1) Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre of Drug Research, Leiden University, The Netherlands, (2) Department of Pharmacy, Ghent University Hospital, Ghent, Belgium, (3) Heymans Institute of Pharmacology and Department of Pediatric Intensive Care, (4) Department of Pediatrics, Division of Neonatology, Erasmus MC – Sophia Children’s Hospital, Rotterdam, The Netherlands, (5) Department of Development and Regeneration, KU, Leuven, Belgium, (6) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
Objectives: Active secretion by renal transporters, largely contributes to the elimination of drugs that are substrates for these transporters, however, there is limited information regarding the maturation of their expression and activity throughout the paediatric age-range[1]. This information could lead to more accurate clearance (CL) predictions for drugs that are renally actively secreted and, ultimately, to improved pediatric drug development. Therefore, we aim to combine population PK and PBPK approaches to characterize the maturation of the organic anion transporters 1 and 3 system (OATs), throughout the paediatric age range, using clavulanic acid and amoxicillin as a probe drugs.
Methods: Individual post-hoc CL values for clavulanic acid and amoxicillin were obtained from a population pharmacokinetics (PK) model published by De Cock et al.[4]. This model was based on data collected in 50 critically ill children with ages between 0.08 and 15 years (median of 2.6 years), admitted at the paediatric intensive care unit of the Ghent University Hospital in Belgium[4]. Both compounds were co-administered in a fixed ratio to all patients.
The major route of elimination for clavulanic acid is glomerular filtration (GF)[3] and for amoxicillin a combination between GF and active tubular secretion by OATs[2]. A published physiology-based PK (PBPK) sub-model describing renal clearance (CL)[5] was used in combination with the individual post-hoc CL estimates of the two compounds to derive individual intrinsic CL of OATs (CLint,T), for which a maturation profile throughout the studied pediatric age-range was estimated. To fit the individual post-hoc CL estimates of both compounds, we first derived the typical CL values using the PBPK renal sub-model and then estimated inter-individual variability (IIV) separately for CL through GF (clavulanic acid) and for CL through active tubular secretion (amoxicillin). The parameters in the renal PBPK sub-model rely on published equations that describe the age-related changes of system-specific parameters (i.e., GF rate[6], renal blood flow[7], kidney weight (Simcyp v18), serum albumin concentrations[7]), of drug-specific parameters (i.e., fraction unbound) and the combination parameter (i.e., CLint,T).
The post-hoc CL estimates of clavulanic acid were fitted with the PBPK sub-model including only GF and estimating IIV. In critically ill children CL was found to be augmented[4], therefore, a residual CL term was included, which may account for secondary routes of elimination or the disease status of the patients. The augmented CL through GF was assumed to yield a similar increase in amoxicillin CL as well. The post-hoc CL estimates of amoxicillin were fitted using the PBPK renal sub-model including both augmented GF and active tubular secretion. While fixing the established age-related changes of the system-specific parameters, we estimated the typical CLint,T value and IIV of active tubular secretion. We quantified the maturation profile of OATs by exploring available covariates such as age, postmenstrual age and weight in exponential or sigmoidal relationships on individual CLint,T estimates in a simultaneous fit.
Results: We found that the maturation profile of the OATs was best described by a sigmoid Emax relationship between CLint,T and PMA, for children between 0.08 and 15 years of age. CLint,T was estimated to be 31 ml/h/g kidney in a 15-year-old. At birth, the activity of the OATs is absent (i.e., CLint,T is 0) and reaches half of the maximum capacity of a 15-year-old at 8 months of age (PMA = 74.9 weeks with RSE% of 3%). The median contribution of active tubular secretion to amoxicillin renal CL for the studied pediatric population is 33% (range: 12% – 56%).
CL of clavulanic acid was estimated to be 2-fold higher than the expected CL based on GF in a healthy pediatric population. This is in line with previous findings showing increase in CL in critically ill children[4].
Conclusions: We are the first to use a combined population PK and PBPK approach to quantify a maturation function for the in vivo active tubular secretion CL throughout a broad paediatric age-range. In the future, the contribution of age-related changes in transporters’ protein expression and activity, and number of proximal tubule cells per gram kidney to the in vivo CLint,T could be further disentangled.
References:
[1] Cristea S. et al., PAGE 26 (2017) Abstr 7207 [www.page-meeting.org/?abstract=7207].
[2] Parvez M. M. et al., Antimicrob. Agents Chemother., 2018 Aug; 62(9) e00512-18.
[3] Horber F. F. et al., Antimicrob. Agents Chemother., 1986, Apr; 29(4): 614–619.
[4] De Cock P. A. J. G. et al., Antimicrob. Agents Chemother., 2015 Nov; 59(11):7027–7035.
[5] Rowland Yeo K. et al., Expert Rev Clin Pharmacol, 2011 Mar;4(2):261-74.
[6] Salem F. et al., Clin Pharmacokinet., 2014 Jul;53(7):625-36
[7] Johnson T.N. et al., Clin Pharmacokinet., 2006; 45(9):931-956
Reference: PAGE 28 (2019) Abstr 9121 [www.page-meeting.org/?abstract=9121]
Poster: Drug/Disease Modelling - Paediatrics