Introduction: Adverse drug reactions (ADRs) are among the leading causes of death, and frequently associated with drug-gene interactions (DGIs). In addition to pharmacogenomic programs for implementation of genetic preemptive testing into clinical practice, mathematical modeling can help to understand, quantify and predict the effects of DGIs in vivo. Moreover, modeling can contribute to optimize prospective clinical drug trial activities and to reduce DGI-related ADRs.
Areas covered: Approaches and challenges of mechanistical DGI implementation and model parameterization are discussed for population pharmacokinetic and physiologically based pharmacokinetic models. The broad spectrum of published DGI models and their applications is presented, focusing on the investigation of DGI effects on pharmacology and model-based dose adaptations.
Expert opinion: Mathematical modeling provides an opportunity to investigate complex DGI scenarios and can facilitate the development process of safe and efficient personalized dosing regimens. However, reliable DGI model input data from in vivo and in vitro measurements are crucial. For this, collaboration among pharmacometricians, laboratory scientists and clinicians is important to provide homogeneous datasets and unambiguous model parameters. For a broad adaptation of validated DGI models in clinical practice, interdisciplinary cooperation should be promoted and qualification toolchains must be established.
Keywords: Dose adaptation; drug–drug–gene interaction; drug–gene interaction; mathematical modeling; pharmacodynamics; pharmacogenetics; pharmacokinetics; physiologically based pharmacokinetics; population pharmacokinetics.