Europe – Guideline on the reporting of physiologically based pharmacokinetic (PBPK) modelling and simulation

Executive summary
A growing number of regulatory submissions include physiologically based pharmacokinetic (PBPK) models that require the use of specialised software platforms. While PBPK modelling is presently mentioned in several existing EMA guidelines, this is the first to specifically provide detailed advice on what to include in a PBPK modelling report including, in particular, details of the predictive performance of the drug model. If PBPK modelling is intended to support a regulatory decision, the PBPK platform needs to be qualified for the intended use. This document, therefore, also aims to clarify which supportive data are expected in order to qualify a PBPK platform, accordingly.

1. Introduction
For the purpose of this guideline, a PBPK model is defined as a mathematical model that simulates the concentration of a drug over time in tissue(s) and blood, by taking into account the rate of the drug’s absorption into the body, distribution in tissues, metabolism and excretion (ADME) on the basis of interplay between physiological, physicochemical and biochemical determinants. Presently, the main purposes of PBPK models in regulatory submissions are to qualitatively and quantitatively predict drug-drug interactions (DDIs) and to support initial dose selection in paediatric and first-in-human trials.
However, it is expected that the extent of use of PBPK modelling will expand as additional scientific evidence on e.g. physiology parameters in different populations (system knowledge) is gained and confidence in the utility of PBPK models increases.
The majority of PBPK regulatory submissions currently involve the use of commercially available specialised PBPK platforms, i.e. collections of computer programs and included system data. However, the recommendations in this guidance apply to both commercially available platforms and noncommercial/in-house built platforms. In any event, when used for regulatory decisions, simulations performed using PBPK platforms need to be carefully assessed regarding (1) the ability of the platform to adequately perform simulations of the intended type (i.e., the PBPK platform needs to be qualified for the intended use with well characterised in vivo data) (see Appendix 1) and (2) the predictive performance of the specific drug models (see Appendix 2). To allow for such assessment the submitted PBPK report should include the validity and biological plausibility of input parameters, the
uncertainty around the determination or prediction of parameter values, clarity on the model building and optimisation processes, and a discussion of the consequences of the assumptions made. The level of the evaluations depends on how much weight of evidence the PBPK simulation will have in the decision making i.e. the regulatory impact (see Appendix 1).

If PBPK modelling is used in the development of an investigational drug, it is strongly recommended to use the opportunity to optimally design clinical pharmacology studies that can provide data to progressively improve the model and support the planned model applications.

For the qualification of PBPK platforms for an intended purpose, Committee for Medicines for Human Use (CHMP) scientific advice (Qualification of novel methodologies for drug development: guidance to applicants EMA/CHMP/SAWP/72894/2008/Rev.3) may be sought. Qualification may also be supplied in a given regulatory submission where the PBPK modelling is applied. Qualification may also be supported by, e.g. peer reviewed literature. Seeking CHMP Scientific Advice for additional guidance on the use of PBPK modelling and simulation in support of regulatory decisions is encouraged…