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Published in: Drugs in R&D 1/2024

Open Access 27-11-2023 | Dextromethorphan | Original Research Article

Drug–Drug Interaction Studies of Esmethadone (REL-1017) Involving CYP3A4- and CYP2D6-Mediated Metabolism

Authors: Nicola Ferri, Sara De Martin, James Stuart, Sergio Traversa, Franco Folli, Marco Pappagallo, Cedric O’Gorman, Clotilde Guidetti, Andrea Mattarei, Charles E. Inturrisi, Paolo L. Manfredi

Published in: Drugs in R&D | Issue 1/2024

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Abstract

Background and Objective

Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is the opioid inactive dextro-isomer of racemic methadone. Esmethadone is a low potency N-methyl-D-aspartate (NMDA) receptor channel blocker with higher affinity for GluN2D subtypes. Esmethadone showed robust, rapid, and sustained antidepressant effects in patients with major depressive disorder (MDD) with inadequate response to ongoing serotonergic antidepressant treatment.

Methods

Here we described the results of in vitro and phase 1 clinical trials aimed at investigating the esmethadone metabolism and possible drug-drug interactions.

Results

Esmethadone is primarily metabolized to EDDP (2-ethylene-1,5-dimethyl-3,3-diphenylpyrrolidine) by multiple enzymes, including CYP3A4/5 and CYP2B6. In vitro studies showed that esmethadone inhibits CYP2D6 with IC50 of 9.6 μM and is an inducer of CYP3A4/5. The clinical relevance of the inhibition of CYP2D6 and the induction of CYP3A4 were investigated by co-administering esmethadone and dextromethorphan (a substrate for CYP2D6) or midazolam (a substrate for CYP3A4) in healthy volunteers. The administration of esmethadone at the dosage of 75 mg (which is the loading dose administered to patients in MDD clinical trials) significantly increased the exposure (AUC) of both dextromethorphan and its metabolite dextrorphan by 2.71 and 3.11-fold, respectively. Esmethadone did not modify the pharmacokinetic profile of midazolam, while it increased Cmax and AUC of its metabolite 1′-hydroxymidazolam by 2.4- and 3.8-fold, respectively. A second study evaluated the effect of the CYP3A4 inhibitor cobicistat on the pharmacokinetics of esmethadone. Cobicistat slightly increase (+32%) the total exposure (AUC0–inf) of esmethadone.

Conclusions

In summary, esmethadone demonstrated a negligible effect on CYP3A4 induction and its metabolism was not meaningfully affected by strong CYP3A4 inhibitors while it increased exposure of CYP2D6-metabolized drugs.
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Metadata
Title
Drug–Drug Interaction Studies of Esmethadone (REL-1017) Involving CYP3A4- and CYP2D6-Mediated Metabolism
Authors
Nicola Ferri
Sara De Martin
James Stuart
Sergio Traversa
Franco Folli
Marco Pappagallo
Cedric O’Gorman
Clotilde Guidetti
Andrea Mattarei
Charles E. Inturrisi
Paolo L. Manfredi
Publication date
27-11-2023
Publisher
Springer International Publishing
Published in
Drugs in R&D / Issue 1/2024
Print ISSN: 1174-5886
Electronic ISSN: 1179-6901
DOI
https://doi.org/10.1007/s40268-023-00450-6

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