2010 - Berlin - Germany

PAGE 2010: Applications- CVS
Anne-Kristina Mercier

Physiologically-Based Pharmacokinetic (PBPK) Modelling of Bisoprolol in Adults and Children and External Model Validation in a Paediatric Clinical Trial

A.-K. Frobel, S. Ramusovic, S. Läer

University of Duesseldorf, Department of Clinical Pharmacy and Pharmacotherapy, Germany

Objectives: Although beta-adrenoceptor-blockers have been proven to reduce morbidity and mortality in adult congestive heart failure, there is not enough evidence to recommend or discourage their use in children; neither is sufficient pharmacokinetic data available (Frobel et al. 2008). The aim of our work was therefore to investigate the pharmacokinetics of the beta-1-selective beta-blocker bisoprolol creating both a PBPK model and clinical data in order to provide scientific grounds for dosing in future clinical trials..

Methods: A PBPK model for bisoprolol in adults was created using PK-Sim® software. Main elimination pathways were glomerular filtration and hepatic metabolism via CYP3A4. The model was fitted to adult pharmacokinetic profiles from literature and was then shown to represent healthy volunteer profiles created in our research group. The PK-Sim® clearance scaling module was then used to adapt bisoprolol clearance to age, and pharmacokinetics were predicted for virtual paediatric populations covering the age range from newborns to 18-year-olds. Pharmacokinetic parameters were analysed for different paediatric age groups. We then conducted a clinical trial at Duesseldorf and Hamburg university hospital investigating the pharmacokinetics of bisoprolol in children in order to create experimental data for model validation.

Results: The PBPK-model adaequately described the pharmacokinetics of bisoprolol in adults. Clearance scaling predicted dynamic changes of total bisoprolol clearance over age compared to adult values with a minimum body-weight normalised clearance in the newborns and a maximum in the one- to four-year-old. These predictions for virtual populations will now be compared to pharmakokinetic profiles in “real” paediatric patients (clinical trial ongoing at time of abstract submission).

Conclusions: We present a PBPK model for bisoprolol in adults representing literature as well as own experimental data. This model was adapted to age-dependent changes in physiology and was used to predict bisoprolol pharmacokinetics in paediatric populations. These predictions are currently evaluated in a clinical pharmacokinetic trial. The results of our work may contribute to establish rational dosing in future paediatric trials investigating bisoprolol in children.

[1] Frobel AK, Hulpke-Wette M, Schmidt KG, Läer S. Beta-blockers for congestive heart failure in children. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD007037.

Reference: PAGE 19 (2010) Abstr 1780 [www.page-meeting.org/?abstract=1780]
Poster: Applications- CVS