Juri Solodenko (1), Christian Diedrich (1), Sebastian Frechen (1), Jan-Frederik Schlender (1), Michael Sevestre (2), Rolf Burghaus (1)
(1) Bayer AG, Systems Pharmacology & Medicine, (2) Design2Code Inc
Objectives: The recently issued draft guideline on physiologically-based pharmacokinetic modeling (PBPK) by the European Medicines Agency (EMA) [1] demands the qualification of the intended use related to the PBPK platform for any type of simulation scenario (e.g. CYP3A4 inhibition, pediatric scaling in primarily renally cleared drugs, etc.) in regulatory submissions. Once such a type of scenario is qualified for its use, changes in the software platform (e.g. adjusted or extended model structure, changed parameterization of a model, etc.) require requalification. The objective was to develop a technical concept of automatic requalification of the type of scenario.
Methods: PK-Sim® as part of the Open Systems Pharmacology (OSP) suite [2] is a well-established PBPK tool widely used for more than a decade. It offers different structural models together with relevant physiological and molecular database information for PBPK modeling of small and large molecules in different animal species and human populations. MoBi® can directly use PBPK models created in PK-Sim® but is especially designed for the de novo construction, import, or extension of systems biology and pharmacology models in an (extendible) ordinary differential equation framework. Generally, a certain type of scenario consists of multiple simulations involving a variety of PBPK drug models. A technical concept of its requalification with every new software release was developed.
Results: For a specific type of scenario a software processable “Qualification Plan” is constructed semi-automatically. It consists of:
- A minimal amount of information required to setup all simulations for the intended type of scenario in the Open Systems Pharmacology Suite. This includes the information on primary input parameters (e.g. molecular properties like molecular weight, lipophilicity, etc.), additional model building step (e.g. instructions for incorporating a-posterior knowledge via estimation of unknown parameters from clinical data) of the respective PBPK drug models involved in the particular scenario. Additionally, required input for system parameters (e.g. demographic characteristics) is provided.
- A list of differences between used model values and default values stored in the physiological and molecular OSP databases for the combination of inputs above.
The execution of the “Qualification Plan” produces:
- A report on the evaluation of the individual PBPK drug models with experimental data sets (i.e. standard goodness-of-fit plots, visual predictive checks).
- A comprehensive qualification report for the type of scenario including a predefined set of qualification measures assessing predictive performance (e.g. root-mean-square deviation (RMSD), geometric mean fold error (GMFE), etc.) and charts (e.g. observed vs. predicted data for selected pharmacokinetic parameters – e.g. AUC ratio, Cmax ratio, etc.).
Conclusions: A technical concept is presented to produce comprehensive (re-)qualification reports automatically. This enables an efficient assessment both for sponsors and regulatory bodies and thereby provides full traceability and transparency of all steps. (Re-)Qualification reports can be generated and distributed for every for every new version of the Open Systems Pharmacology Suite.
References:
[1] European Medicines Agency. Guideline on the qualification and reporting of physiologically based pharmacokinetic (PBPK) modelling and simulation (2016).
[2] www.open-systems-pharmacology.org
Reference: PAGE 27 (2018) Abstr 8680 [www.page-meeting.org/?abstract=8680]
Poster: Methodology - Other topics