Accuracy of plasma clearance scaling from adults to children using pathway-specific covariate models: a systematic investigation using a physiologically-based pharmacokinetic workflow
Calvier EAM(1), Krekels EHJ(1), Välitalo PAJ(1), Johnson TN(2), Rostami-Hodjegan A(2,3), Tibboel D(4), Van Der Graaf PH(1,5), Danhof M(1), Knibbe CAJ(1,6)
1 Division of Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands; 2 Simcyp Limited, Sheffield, UK; 3 Manchester Pharmacy School, University of Manchester, Manchester, UK; 4 Intensive Care and Department of Pediatric Surgery, Erasmus University Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands; 5 QSP, Certara, Canterbury, United Kingdom; 6 Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
Objectives: Pathway-specific covariate models (PSCMs) have been proposed to scale plasma clearance (CLp) in paediatrics [1-2]. This method requires the development of a PSCM describing the maturation of CLp using a model drug. Then, this PSCM is used to predict the maturation of CLp of another drug (test drug) sharing the same elimination pathway. As the accuracy of this method has not been systematically investigated, the aim of this project was to define conditions for which PSCMs lead to accurate CLp scaling from adult to paediatric patients.
Methods: In R, ‘true’ CLp was simulated using PBPK principles [3] for 7560 hypothetical drugs either binding to human serum albumin (HSA) or alpha-1 acid glycoprotein (AAG) with a wide range of fraction unbound (fu), extraction ratio (ER) and blood to plasma ratio. For each hypothetical drug, metabolism by 1 isoenzyme (A) or 2 isoenzymes (A and B) was investigated for 15 different hepatic isoenzymes A and B in children from 1 day to 15 years, assuming different fractions metabolized by isoenzyme A in adults (fmA-adults). PSCMs were developed and used for scaling CLp by metabolism by isoenzyme A only. Prediction errors (PE) between ‘true’ CLp and CLp scaled from adults to children with PSCM was computed. Scenarios where PSCM systematically leads to accurate predictions (all PEs within +/-30%) in all investigated ages were defined.
Results: For each of the 15 isoenzymes investigated, the accuracy of CLp scaling across the entire paediatric age range was found to be dependent on the properties of the model drug and test drug. The drug properties best discriminating between accurate and inaccurate CLp predictions in all ages were the type of binding plasma protein, the fmA-adults, the ER of the model drug, and the difference in fu and in ER between the test drug and the model drug. For HSA bound drugs, lower ER of the model drug and test drug yielded more accurate scaling. This accuracy decreased as the ER of the test drug increased compared to the ER of the model drug. For drugs eliminated by two isoenzymes, the accuracy of PSCM decreased with decreasing fmA-adults. For AAG bound drugs, PSCM generally led to inaccurate CLp predictions.
Conclusions: PSCM can be used to accurately scale CLp from adults to children as young as 1 day for HSA bound drugs undergoing hepatic metabolism, but is limited to specific combinations of model drug and test drug properties.
References:
[1] E. H. J. Krekels, M. Neely, E. Panoilia, D. Tibboel, E. Capparelli, M. Danhof, M. Mirochnick, and C. A J. Knibbe, “From pediatric covariate model to semiphysiological function for maturation: part I-extrapolation of a covariate model from morphine to Zidovudine.,” CPT pharmacometrics Syst. Pharmacol., vol. 1, no. October, p. e9, Jan. 2012.
[2] E. H. J. Krekels, T. N. Johnson, S. M. den Hoedt, a Rostami-Hodjegan, M. Danhof, D. Tibboel, and C. A J. Knibbe, “From Pediatric Covariate Model to Semiphysiological Function for Maturation: Part II-Sensitivity to Physiological and Physicochemical Properties.,” CPT pharmacometrics Syst. Pharmacol., vol. 1, no. October, p. e10, Jan. 2012.
[3] E. A. M. Calvier, E. H. J. Krekels, P. A. J. Välitalo, A. Rostami-Hodjegan, D. Tibboel, M. Danhof, and C. A. J. Knibbe, “Allometric Scaling of Clearance in Paediatric Patients: When Does the Magic of 0.75 Fade?,” Clin. Pharmacokinet., pp. 1–13, Aug. 2016.
