Host: The Japanese Society of Toxicology
Name : The 47th Annual Meeting of the Japanese Society of Toxicology
Date : 2020 -
[Background, Objective] Cyclophosphamide (CPM) is a prodrug of alkylating agent activated by CYP2B6. Clinical trials showed that polymorphism of CYP2B6 affected on both therapeutic effects and adverse effects of CPM. However, drug interaction (DI) between CPM and CYP inhibitor has not been reported. To elucidate potential DIs between representative CYP inhibitors and CPM, we assessed the inhibitory profiles of these inhibitors by in vitro cocktail experiments and analyzed adverse events caused by a combination of these drugs and CPM which is reported in Japanese Adverse Drug Event Report database (JADER) and FDA Adverse Event Reporting System (FAERS).
[Method] Mixed substrates for 8 CYP isoforms (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A) were incubated with representative CYP inhibitors in human liver microsome. Specific metabolites were measured by LC-MS/MS and evaluated inhibitory potentials of the inhibitors. Proportional Reporting Ratio (PRR) was calculated based on JADER (2014 to 2019) and FAERS (2015 to 2019) to estimate DIs between CPM and inhibitor in clinical.
[Results, Discussion] Voriconazole (VCZ) most strongly inhibited CYP2B6 (IC50 : 0.12 μM) among the isoforms. PRR of neutropenia, known as a typical adverse effect of CPM, was calculated as 2.83 (in JADER) and 10.7 (in FAERS). Both PRR values were significantly decreased to 0.71 and 4.58 by treating with VCZ concomitantly. These results suggested that VCZ decreased the adverse effect of CPM by CYP2B6 inhibition. The therapeutic effects of CPM may also be decreased by co-treatment with VCZ.
