SY10-3 - Factors Influencing the Onset of Chemotherapy-Induced Adverse Events Including Drug-Drug Interaction

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It is important for cancer chemotherapy to maintain effective response with minimizing undesired drug effects. Individual differences of pharmacokinetics (PK) and pharmacodynamics (PD) of anticancer drugs contribute a great deal to the development of adverse events. With regard to PK change, decrease in renal clearance due to renal failure or drug-drug interaction is one of the most serious problem for drugs mainly excreted by the kidney. Folic acid analogs are typical drugs excreted by the kidney. Recently, we indicated that pemetrexed, one of the folic acid analogs, is a superior substrate to methotrexate for hOAT3 (SLC22A8), and nonsteroidal anti-inflammatory drugs (NSAIDs) could cause drug-drug interaction via renal tubular transport by OAT3 when attaining their high plasma concentrations 1). Incidentally, almost all of small molecule anticancer drugs, which targets intracellular signaling pathway, are metabolized by hepatic cytochrome P450 (CYP) 3A. Strong inhibitors of CYP3A are sometimes used together with the small molecular drugs and increase their plasma concentration, which results in increased risk of toxicities. We previously showed that strong CYP3A inhibitor, itraconazole, appeared to exacerbate peripheral neuropathy and thrombocytopenia caused by bortezomib, a proteasome inhibitor 2). Furthermore, we found out that carboplatin-induced severe allergy after multiple dose of the drugs accompanied the change in immunological reaction, which was obviously confirmed by basophil activation 3), whereas a toxicological study focused on PD change during chemotherapy is still limited.In this symposium, we will summarize our recent findings about the risk of chemotherapy-induced toxicities, which involves the changes in PK/PD of anticancer drugs in clinical settings.1) Kurata T et al., Drug Metab Pharmacokinet (2014)2) Iwamoto T et al., Pharmacotherapy (2010)3) Iwamoto T et al., Biol Pharm Bull (2012)