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Bridging physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) analyses in paediatric drug development: A case study based on intravenous esomeprazole
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics)
2018 (English)Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
Abstract [en]

Introduction: Model-based approaches are implemented in obligatory steps of paediatric 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.

Aims: 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 and NONMEM, respectively. Adult models were firstly developed and then verified towards adult clinical data. 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. The children models were used to simulate approved dosage schedules in children and predict area under the plasma concentration-time curve extrapolated to infinity (AUCinf). Exposure-matching analysis for paediatric dose selection was used, where the target was to match the AUCinf in adults (2.67 molh/L). Dose optimizations to the targeted AUCinf were carried out with both PBPK and PopPK paediatric models. 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 differences were 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.

Place, publisher, year, edition, pages
2018. , p. 17
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-355105OAI: oai:DiVA.org:uu-355105DiVA, id: diva2:1224142
External cooperation
Pharmetheus AB, Uppsala, Sweden
Subject / course
Pharmaceutical Biosciences
Educational program
Master of Science Programme in Pharmacy
Presentation
2018-05-30, C8:321, Husargatan, 752 37 Uppsala, Uppsala, 15:15 (English)
Supervisors
Examiners
Available from: 2018-06-27 Created: 2018-06-26 Last updated: 2018-06-27Bibliographically approved

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