Strategic proposals for avoiding toxic interactions with drugs for clinical use during development and after marketing of a new drug--proposals for designing non-clinical and clinical studies--is the non-clinical study useful?
Since sorivudine incident has happened in Japan in 1993, an adverse drug-drug interaction has been of special meanings at each step of new drug development including the discovery step, NDA process, and on market. While it is known that several mechanisms are involved in the drug-drug interactions, the mechanisms related to drug metabolism are 1) inhibition of drug metabolizing enzymes, 2) induction of the enzymes, 3) drug absorption, 4) renal excretion, 5) hepatic transport, and 6) protein binding (displacement) interaction. In this report, proposals to avoid serious/lethal drug-drug interactions are presented with the examples. The proposals are: 1) To estimate the drug-drug interactions in consideration of the mechanisms reported so far, 2) To be especially careful for drugs with a small therapeutic index and severe/lethal toxicity, 3) To estimate the drug-drug interactions in consideration of physiological factors of patients, who receive drugs in combination, 4) Not to leave the mechanism unclear, when some data, which do not deny the critical drug-drug interactions, were obtained, and 5) To conduct the drug-drug interaction studies in humans in careful consideration of the safety.
Ozawa
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Upjohn Pharmaceuticals Limited, Tsukuba Research Laboratories, Ibaraki, Japan.
D000818:Animals; D015195:Drug Design; D004341:Drug Evaluation / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D011358:Product Surveillance, Postmarketing; D018570:Risk Assessment