Читать книгу Transporters and Drug-Metabolizing Enzymes in Drug Toxicity - Albert P. Li - Страница 17

While the conventional preclinical and clinical safety evaluation are essential to the assessment of drug safety, additional considerations are needed to avoid the occurrence of idiosyncratic drug toxicity. I have previously proposed that drug safety assessment requires a comprehensive, multidisciplinary approach (8, 9) with input from pharmacologists, toxicologists, epidemiologists, population geneticists, and especially drug metabolism/pharmacokinetics (DMPK) experts to provide insight toward the possible risk factors discussed above.

Key parameters to be considered for drug safety evaluation based on this comprehensive approach include the following: (i) Pharmacology: Possible toxicity due to drug–target interactions, including interactions with unintended molecular targets, or with molecular targets in unintended organs. (ii) Chemistry: Chemical scaffolding and side chains with safety concerns. (iii) Toxicology: Toxicity in animals in vivo, and in relevant animal and human cells in culture. (iv) DMPK: Safety concerns due to toxification or detoxification, organ distribution, clearance, and pharmacokinetic drug–drug interactions. (v) Risk factors: Physiological, environmental, and genetic factors that may enhance a patient's susceptibility. It is proposed that this integrated, multidisciplinary approach to safety evaluation may enhance the accuracy of the prediction of drug safety and thereby the efficiency of drug development (8, 9).