Innovations, Opportunities and Challenges for Predicting Alteration in Drug Metabolizing Enzymes and Transporters Activity in Specific Populations .

Drug metabolizing enzymes and transporters (DMETs) are key regulators of pharmacokinetics (PK), efficacy and toxicity of therapeutics. Over the past two decades, significant advancements in in vitro methodologies, targeted proteomics, in vitro-to-in vivo extrapolation (IVIVE) methods and integrated computational approaches such as physiologically based pharmacokinetic (PBPK) modeling have unequivocally contributed to improving our ability to quantitatively predict the role of DMETs in ADME (absorption, distribution, metabolism, and excretion) and drug-drug interactions (DDIs). However, the paucity of data regarding alterations in DMETs activity in specific populations such as pregnant individuals, lactation, pediatrics, geriatrics, organ impairment and disease states such as, cancer, kidney and liver diseases, and inflammation has restricted our ability to realize the full potential of these recent advancements. We envision that a series of carefully curated articles in a special supplementary issue of Drug Metabolism and Disposition will summarize the latest progress in in silico , in vitro , and in vivo approaches to characterize alteration in DMET activity and quantitatively predict drug disposition in specific populations. In addition, the supplementary issue will underscore the current scientific knowledge gaps which present formidable barriers to fully understand the clinical implications of altered DMET activity in specific populations and highlight opportunities for multistakeholder collaboration to advance our collective understanding of this rapidly emerging area. Significance Statement This commentary highlights current knowledge and identifies gaps and key challenges in understanding the role of DMETs in drug disposition in specific populations. With this commentary for the special issue in Drug Metabolism and Disposition, authors intend to increase interest and invite potential contributors whose research is focused or has aided in expanding the understanding around the role and impact of DMETs in drug disposition in specific populations.