Carboxylesterase 1-Based Drug-Drug Interaction Potential of Remimazolam: In-Vitro Studies and Literature Review.

Background: The ultra-short-acting benzodiazepine remimazolam, approved for procedural sedation and general anesthesia, is inactivated by carboxylesterase 1 (CES1).

Objective: Remimazolam´s involvement in CES1-mediated drug-drug interactions (DDIs) was investigated.

Methods: Possible interactions of remimazolam were studied in co-exposure experiments with eleven different drugs. Further, substrates and inhibitors of CES1, identified in the literature, were evaluated for possible in-vivo inhibition using pharmacokinetic and Ki or IC₅₀ values. Compounds with only one published inhibitory concentration and CES1 substrates lacking inhibition data were assigned conservative Ki values.

Results: In human liver homogenates and/or blood cells, remimazolam showed no significant inhibition of esmolol and landiolol metabolism, which, in turn, at up to 98 and 169 μM, respectively, did not inhibit remimazolam hydrolysis by human liver homogenates. In human liver S9 fractions, IC₅₀ values ranged from 0.69 μM (simvastatin) and 57 μM (diltiazem) to > 100 μM (atorvastatin) and, for the remaining test items (bupropion, carvedilol, nelfinavir, nitrendipine, and telmisartan), they ranged from 126 to 658 μM. Remifentanil was ineffective even at 1250 μM. Guidance-conforming evaluation revealed no relevant drug-drug interactions with remimazolam via CES1. The algorithm-based predictions were consistent with human study data. Among CES1 inhibitors and substrates identified in the literature, only dapsone and rufinamide were found to be possible in-vivo inhibitors of remimazolam metabolism.

Conclusion: Data and analyses suggest a very low potential of remimazolam for pharmacokinetic DDIs mediated by CES1. The theoretical approach and compiled data are not specific to remimazolam and, hence, applicable in the evaluation of other CES1 substrates.