Abstract
The utilization of mathematical modeling and simulation in drug development encompasses multiple mathematical techniques and the location of a drug candidate in the development pipeline. Historically speaking they have been used to analyze experimental data (i.e., Hill equation) and clarify the involved physical and chemical processes (i.e., Fick laws and drug molecule diffusion). In recent years the advanced utilization of mathematical modeling has been an important part of the regulatory review process. Physiologically based pharmacokinetic (PBPK) models identify the need to conduct specific clinical studies, suggest specific study designs and propose appropriate labeling language. Their application allows the evaluation of the influence of intrinsic (e.g., age, gender, genetics, disease) and extrinsic [e.g., dosing schedule, drug-drug interactions (DDIs)] factors, alone or in combinations, on drug exposure and therefore provides accurate population assessment. A similar pathway has been taken for the assessment of drug safety with cardiac safety being one the most advanced examples. Mechanistic mathematical model-informed safety evaluation, with a focus on drug potential for causing arrhythmias, is now discussed as an element of the Comprehensive in vitro Proarrhythmia Assay. One of the pillars of this paradigm is the use of an in silico model of the adult human ventricular cardiomyocyte to integrate in vitro measured data. Existing examples (in vitro—in vivo extrapolation with the use of PBPK models) suggest that deterministic, epidemiological and clinical data based variability models can be merged with the mechanistic models describing human physiology. There are other methods available, based on the stochastic approach and on population of models generated by randomly assigning specific parameter values (ionic current conductance and kinetic) and further pruning. Both approaches are briefly characterized in this manuscript, in parallel with the drug-specific variability.
Highlights
Mechanistic Modeling and Simulation Approach in the Process of Drug Development in Light of the Recent Changes to Food and Drug Administration (FDA)/European Medicines Agency (EMA)/PMDA RegulationsThe mathematical modeling and simulation (M&S) approach has held its place in the drug development process since the very beginning
Special interest has been given to physiologically based pharmacokinetic (PBPK) modeling defined by WHO as “quantitative descriptions of the absorption, distribution, metabolism, and excretion (ADME) of chemicals in biota based on interrelationships among key physiological, biochemical and physicochemical determinants of these processes”1
A physiologically based pharmacokinetic approach is based on a combination of the physiology, environment, and drug specific information
Summary
The mathematical modeling and simulation (M&S) approach has held its place in the drug development process since the very beginning. The variability is already observed at the stage of in vitro measurements, e.g., in drug effects on the ventricular ion currents or in the effects on human stem cell-derived cardiomyocytes (iPSC-CM) which differ in channel gene expression profiles and patterns of arrhythmic events after testing with the same model drug (Elkins et al, 2013; Blinova et al, 2017). The models proved successful for studying cardiac physiology and understanding pathological changes (e.g., arrhythmias) associated with diseases over the last decades and currently they are used in the safety assessment of drugs (Mirams et al, 2012; Roberts et al, 2012; Davies et al, 2016; Gintant et al, 2016). All of the approaches stem from the belief that the “average patient” does not exist and a traditional model cannot accurately explain the observed differences between patients
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