2018 - Montreux - Switzerland

PAGE 2018: Drug/Disease modelling - Paediatrics
Erik Sjögren

Bridging physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) analyses in paediatric drug development: A case study based on intravenous esomeprazole

Wannee Kantasiripitak (1), Erik Sjögren (1)(2) and Mats Magnusson (2)

(1) Uppsala University, Sweden, (2) Pharmetheus, Sweden

Objectives: Model-based approaches are implemented in obligatory steps of pediatric drug development. Physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) are two modelling methods often proposed to characterize paediatric pharmacokinetic (PK) and to support clinical trial design in children [1]. The aims of this study were to adopt the two well established modelling and simulation (M&S) techniques, PBPK and PopPK, for scaling the PK characteristics of esomeprazole to a paediatric population and to establish complementary and synergistic modelling approaches for the selection of an optimal dosing regimen in children.

Methods: PBPK and PopPK models were built using PK-Sim [2] and NONMEM [3], respectively. Adult models were firstly developed [4] and then verified towards adult clinical data [5]. Paediatric models were refined and extrapolated from the verified adult models with systemic ontogeny for the PBPK method and allometric scaling for the PopPK method [6]. The children models were used to simulate approved dosage schedules in children [7] and predict area under the plasma concentration-time curve extrapolated to infinity (AUCinf). Exposure-matching analysis for paediatric dose selection was used [8], where the target was to match the AUCinf in adults (2.67 umol•h/L). Dose optimizations to the targeted AUCinf were carried out with both PBPK and PopPK paediatric models [9]. Determinations of weight-based cutoff regimens were performed in NONMEM with PBPK and PopPK based approaches and various numbers of weight cutoff.

Results: The PBPK and the PopPK adult models provided adequate descriptions of the esomeprazole’s PK characteristics in adults. The predicted outcomes of the paediatric models were similar for children > 1 year. Some difference was observed for children < 1 year probably due to that maturation of metabolic activity was not accounted for in the PopPK paediatric model. With the approved dosing regimen both paediatric models predicted higher plasma exposure in children than reported for adults after a 20 mg dose. Consequently, the optimal doses were estimated to be lower than the approved doses. The deviation from the target AUCinf decreased dramatically when using optimal dosing regimens compared to the labelled dose. Even though additional body weight dose switches did not result in a meaningful improvement of the exposure matching, the between subject variability decreased for dosing regimens with one body weight based dose switch.

Conclusions: This study demonstrates how dose-optimization algorithms can be applied to both PopPK and PBPK derived models. In line with regulatory recommendations these complementary results can be used as support in selection of dosing regimen in children.

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[6] W. Zhou, T.N. Johnson, H. Xu, S. Cheung, K.H. Bui, J. Li, N. Al-Huniti, D. Zhou, Predictive Performance of Physiologically Based Pharmacokinetic and Population Pharmacokinetic Modeling of Renally Cleared Drugs in Children, CPT Pharmacomet. Syst. Pharmacol. 5 (2016) 475–483. doi:10.1002/psp4.12101.
[7] AstraZeneca, NEXIUM® I.V. (esomeprazole sodium), (2014). https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021689s030lbl.pdf.
[8] FDA Clinical Pharmacology Review for Nexium IV (Esomeprazole Sodium), 2010. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM258684.pdf.
[9] S. Jönsson, M.O. Karlsson, Estimation of dosing strategies aiming at maximizing utility or responder probability, using oxybutynin as an example drug, Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci. 25 (2005) 123–132. doi:10.1016/j.ejps.2005.02.004.  

Reference: PAGE 27 (2018) Abstr 8635 [www.page-meeting.org/?abstract=8635]
Poster: Drug/Disease modelling - Paediatrics
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