Whole-Body Physiologically-Based Pharmacokinetic (WB-PBPK) Modeling of Moxifloxacin (MFX) to Support a Translational Approach in Pediatric Study Design
C. Becker(1), S. Willmann (1), T. Eissing (1), R. Burghaus (2), J. Lippert(1), G. Ahr(2), H. Stass(2)
(1) Bayer Technology Services GmbH, Systems Biology, D-51368 Leverkusen, Germany; (2) Bayer Schering Pharma AG, D-42096 Wuppertal, Germany
Objectives: Pediatric development strategies requested by FDA and EMEA aim for dosing recommendations to maintain efficacy and safety in different age groups. Since established PK methods such as simple allometric scaling show limited predictive power, an alternative approach is applied to design clinical studies in children: the use of a pediatric PBPK model for MFX paying attention to developmental changes.
Methods: An adult WB-PBPK model for MFX is built using the software PK-Sim®. When the simulated plasma concentration-time profiles and clearance pathways reflect adequately the observed data from adults, the physiological and ontogenic changes and the clearance pathways of MFX are scaled to the respective ages using the Clearance Scaling Module of PK-Sim®. The Population Module of PK-Sim® is used to build virtual populations of children from 18 to 0.5 years categorized according to the ICH11 classification. Concentration-time profiles in the different pediatric populations are predicted by the pediatric WB-PBPK model. Based on the predictions, and derived PK parameters, dose and dosing scheme recommendations are developed to maintain exposure and maximum concentrations limits known for efficacy (AUC) and safety (Cmax) in adults.
Results: The WB-PBPK model provides an accurate description of the experimental PK data of MFX in adults. In preschool children and infants between 25 to 80% higher mg/kg doses and/or shorter dosing intervals than those recommended in adults are required to achieve equivalent exposure to adults. The results obtained from the pediatric PBPK model are used to plan first studies in pediatric patients.
Conclusions: The WB-PBPK predictions of pediatric populations enable the rationale knowledge-based development of study designs. The approach uses drug-independent prior information about developmental differences between the pediatric populations and adults. It suited for iterative continuous validation and refinement when clinical data of MFX in pediatric patients becomes available. This knowledge-driven approach strengthens the scientific basis of the pediatric development and is well suited for continuous trial support.
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