Prediction of Drug–Drug Interactions After Esketamine Intranasal Administration Using a Physiologically Based Pharmacokinetic Model

Abstract

A physiologically based pharmacokinetic (PBPK) modeling approach for esketamine and its metabolite noresketamine after esketamine intranasal administration was developed to aid the prediction of drug-drug interactions (DDIs) during the clinical development of esketamine nasal spray (SPRAVATO®). This article describes the development of the PBPK model to predict esketamine and noresketamine kinetics after intranasal administration of esketamine and its verification and application in the prediction of prospective DDIs with esketamine using models of index perpetrator and victim drugs. The intranasal PBPK (IN-PBPK) models for esketamine/noresketamine were constructed in Simcyp® v14.1 by combining the oral and intravenous esketamine PBPK models, with the dose divided in the ratio 57.7/42.3. Verification of the model was based on comparing the pharmacokinetics and DDI simulations with observed data in healthy volunteers. The simulated and observed (171 healthy volunteers) plasma pharmacokinetic profiles of intranasal esketamine/noresketamine showed a good match. The relative contributions of different cytochromes P450 (CYPs), mainly CYP3A4 and CYP2B6, involved in esketamine/noresketamine clearance was captured correctly in the IN-PBPK model using the DDI clinical studies of intranasal esketamine with clarithromycin and rifampicin and a published DDI study of oral esketamine with ticlopidine. The induction potential of esketamine toward CYP3A4 was also well captured. Inhibition of intranasal esketamine in the presence of ticlopidine was predicted to be not clinically relevant. Different scenarios tested with esketamine as a CYP3A4 perpetrator of midazolam also predicted the absence of clinically relevant CYP3A4 interactions. This PBPK model of the intranasal route adequately described the pharmacokinetics and DDI of intranasal esketamine/noresketamine with potential perpetrator and victim drugs. This work was used to support regulatory submissions of SPRAVATO®.