Drug-Drug Interaction Studies of Esmethadone (REL-1017) Involving CYP3A4- and CYP2D6-Mediated Metabolism.
Journal
Drugs in R&D
ISSN: 1179-6901
Titre abrégé: Drugs R D
Pays: New Zealand
ID NLM: 100883647
Informations de publication
Date de publication:
27 Nov 2023
27 Nov 2023
Historique:
accepted:
02
11
2023
medline:
27
11
2023
pubmed:
27
11
2023
entrez:
27
11
2023
Statut:
aheadofprint
Résumé
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. Here we described the results of in vitro and phase 1 clinical trials aimed at investigating the esmethadone metabolism and possible drug-drug interactions. 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 IC 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.
Sections du résumé
BACKGROUND AND OBJECTIVE
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
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
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 IC
CONCLUSIONS
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.
Identifiants
pubmed: 38010591
doi: 10.1007/s40268-023-00450-6
pii: 10.1007/s40268-023-00450-6
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023. The Author(s).
Références
Low Y, Setia S, Lima G. Drug-drug interactions involving antidepressants: focus on desvenlafaxine. Neuropsychiatr Dis Treat. 2018;14:567–80.
pubmed: 29497300
pmcid: 5822840
doi: 10.2147/NDT.S157708
Henningfield J, Gauvin D, Bifari F, Fant R, Shram M, Buchhalter A, et al. REL-1017 (esmethadone; D-methadone) does not cause reinforcing effect, physical dependence and withdrawal signs in Sprague Dawley rats. Sci Rep. 2022;12(1):11389.
pubmed: 35794162
pmcid: 9259683
doi: 10.1038/s41598-022-15055-3
Shram M, Henningfield J, Apseloff G, Gorodetzky C, De Martin S, Vocci F, et al. No meaningful abuse potential in recreational ketamine users of REL-1017 (esmethadone hydrochloride), a new NMDAR antagonist and potential rapid-acting antidepressant. Presented at: American Society of Clinical Psychopharmacology (ASCP) Annual Meeting; Scottsdale (AZ); 31, 2022.
Bettini E, De Martin S, Mattarei A, Pappagallo M, Stahl SM, Bifari F, et al. The N-methyl-D-aspartate receptor blocker REL-1017 (esmethadone) reduces calcium influx induced by glutamate, quinolinic acid, and gentamicin. Pharmaceuticals (Basel). 2022;15(7):882.
pubmed: 35890179
doi: 10.3390/ph15070882
Bettini E, Stahl SM, De Martin S, Mattarei A, Sgrignani J, Carignani C, et al. Pharmacological comparative characterization of REL-1017 (esmethadone-HCl) and other NMDAR channel blockers in human heterodimeric N-methyl-D-aspartate receptors. Pharmaceuticals (Basel). 2022;15(8):997.
pubmed: 36015145
doi: 10.3390/ph15080997
Fava M, Stahl S, Pani L, De Martin S, Pappagallo M, Guidetti C, et al. REL-1017 (esmethadone) as adjunctive treatment in patients with major depressive disorder: a phase 2a randomized double-blind trial. Am J Psychiatry. 2022;179(2):122–31.
pubmed: 34933568
doi: 10.1176/appi.ajp.2021.21020197
Bernstein G, Davis K, Mills C, Wang L, McDonnell M, Oldenhof J, et al. Characterization of the safety and pharmacokinetic profile of D-methadone, a novel N-methyl-D-aspartate receptor antagonist in healthy, opioid-naive subjects: results of two phase 1 studies. J Clin Psychopharmacol. 2019;39(3):226–37.
pubmed: 30939592
doi: 10.1097/JCP.0000000000001035
Meresaar U, Nilsson MI, Holmstrand J, Anggard E. Single dose pharmacokinetics and bioavailability of methadone in man studied with a stable isotope method. Eur J Clin Pharmacol. 1981;20(6):473–8.
pubmed: 7286059
doi: 10.1007/BF00542102
Wolff K, Hay AW, Raistrick D, Calvert R. Steady-state pharmacokinetics of methadone in opioid addicts. Eur J Clin Pharmacol. 1993;44(2):189–94.
pubmed: 8453965
doi: 10.1007/BF00315479
Wolff K, Rostami-Hodjegan A, Shires S, Hay AW, Feely M, Calvert R, et al. The pharmacokinetics of methadone in healthy subjects and opiate users. Br J Clin Pharmacol. 1997;44(4):325–34.
pubmed: 9354306
pmcid: 2042854
doi: 10.1046/j.1365-2125.1997.t01-1-00591.x
Kristensen K, Blemmer T, Angelo HR, Christrup LL, Drenck NE, Rasmussen SN, et al. Stereoselective pharmacokinetics of methadone in chronic pain patients. Ther Drug Monit. 1996;18(3):221–7.
pubmed: 8738759
doi: 10.1097/00007691-199606000-00001
Nilsson MI, Anggard E, Holmstrand J, Gunne LM. Pharmacokinetics of methadone during maintenance treatment: adaptive changes during the induction phase. Eur J Clin Pharmacol. 1982;22(4):343–9.
pubmed: 7106170
doi: 10.1007/BF00548404
Gourlay GK, Cherry DA, Cousins MJ. A comparative study of the efficacy and pharmacokinetics of oral methadone and morphine in the treatment of severe pain in patients with cancer. Pain. 1986;25(3):297–312.
pubmed: 3528988
doi: 10.1016/0304-3959(86)90234-4
Garrido MJ, Troconiz IF. Methadone: a review of its pharmacokinetic/pharmacodynamic properties. J Pharmacol Toxicol Methods. 1999;42(2):61–6.
pubmed: 10924887
doi: 10.1016/S1056-8719(00)00043-5
Ketter TA, Flockhart DA, Post RM, Denicoff K, Pazzaglia PJ, Marangell LB, et al. The emerging role of cytochrome P450 3A in psychopharmacology. J Clin Psychopharmacol. 1995;15(6):387–98.
pubmed: 8748427
doi: 10.1097/00004714-199512000-00002
Moody NB, Smith PL. Proactive changes in nursing work force development in Tennessee. J Nurs Adm. 1997;27(12):4–7.
pubmed: 9418749
doi: 10.1097/00005110-199712000-00003
Gerber JG, Rhodes RJ, Gal J. Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19. Chirality. 2004;16(1):36–44.
pubmed: 14628297
doi: 10.1002/chir.10303
Iribarne C, Berthou F, Baird S, Dreano Y, Picart D, Bail JP, et al. Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. Chem Res Toxicol. 1996;9(2):365–73.
pubmed: 8839037
doi: 10.1021/tx950116m
Foster DJ, Somogyi AA, Bochner F. Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4. Br J Clin Pharmacol. 1999;47(4):403–12.
pubmed: 10233205
pmcid: 2014231
doi: 10.1046/j.1365-2125.1999.00921.x
Wang JS, DeVane CL. Involvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro. Drug Metab Dispos. 2003;31(6):742–7.
pubmed: 12756206
doi: 10.1124/dmd.31.6.742
Kharasch ED, Hoffer C, Whittington D, Sheffels P. Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone. Clin Pharmacol Ther. 2004;76(3):250–69.
pubmed: 15371986
doi: 10.1016/j.clpt.2004.05.003
Bruce RD, Altice FL, Gourevitch MN, Friedland GH. Pharmacokinetic drug interactions between opioid agonist therapy and antiretroviral medications: implications and management for clinical practice. J Acquir Immune Defic Syndr. 2006;41(5):563–72.
pubmed: 16652030
doi: 10.1097/01.qai.0000219769.89679.ec
Gerber JG, Rosenkranz S, Segal Y, Aberg J, D’Amico R, Mildvan D, et al. Effect of ritonavir/saquinavir on stereoselective pharmacokinetics of methadone: results of AIDS Clinical Trials Group (ACTG) 401. A cquir Immune Defic Syndr. 2001;27(2):153–60.
doi: 10.1097/00126334-200106010-00010
Kharasch ED, Bedynek PS, Park S, Whittington D, Walker A, Hoffer C. Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: I. Evidence against CYP3A mediation of methadone clearance. Clin Pharmacol Ther. 2008;84(4):497–505.
pubmed: 19238655
doi: 10.1038/clpt.2008.104
Kharasch ED, Walker A, Whittington D, Hoffer C, Bedynek PS. Methadone metabolism and clearance are induced by nelfinavir despite inhibition of cytochrome P4503A (CYP3A) activity. Drug Alcohol Depend. 2009;101(3):158–68.
pubmed: 19232844
pmcid: 3582041
doi: 10.1016/j.drugalcdep.2008.12.009
Kharasch ED, Hoffer C, Whittington D, Walker A, Bedynek PS. Methadone pharmacokinetics are independent of cytochrome P4503A (CYP3A) activity and gastrointestinal drug transport: insights from methadone interactions with ritonavir/indinavir. Anesthesiology. 2009;110(3):660–72.
pubmed: 19225389
doi: 10.1097/ALN.0b013e3181986a9a
Friedland G, Andrews L, Schreibman T, Agarwala S, Daley L, Child M, et al. Lack of an effect of atazanavir on steady-state pharmacokinetics of methadone in patients chronically treated for opiate addiction. AIDS. 2005;19(15):1635–41.
pubmed: 16184033
doi: 10.1097/01.aids.0000183628.20041.f2
US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry: clinical drug interaction studies: cytochrome P450 enzyme- and transporter-mediated drug interactions. 2020. https://www.fda.gov/media/134581/download . Accessed 13 Nov 2023.
Foster DJ, Somogyi AA, Dyer KR, White JM, Bochner F. Steady-state pharmacokinetics of (R)- and (S)-methadone in methadone maintenance patients. Br J Clin Pharmacol. 2000;50(5):427–40.
pubmed: 11069437
pmcid: 2014413
doi: 10.1046/j.1365-2125.2000.00272.x
Nguyen HQ, Kimoto E, Callegari E, Obach RS. Mechanistic modeling to predict midazolam metabolite exposure from in vitro data. Drug Metab Dispos. 2016;44(5):781–91.
pubmed: 26956641
doi: 10.1124/dmd.115.068601
Mandema JW, Tuk B, van Steveninck AL, Breimer DD, Cohen AF, Danhof M. Pharmacokinetic-pharmacodynamic modeling of the central nervous system effects of midazolam and its main metabolite alpha-hydroxymidazolam in healthy volunteers. Clin Pharmacol Ther. 1992;51(6):715–28.
pubmed: 1611810
doi: 10.1038/clpt.1992.84
Gertz M, Harrison A, Houston JB, Galetin A. Prediction of human intestinal first-pass metabolism of 25 CYP3A substrates from in vitro clearance and permeability data. Drug Metab Dispos. 2010;38(7):1147–58.
pubmed: 20368326
doi: 10.1124/dmd.110.032649
von Richter O, Burk O, Fromm MF, Thon KP, Eichelbaum M, Kivisto KT. Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther. 2004;75(3):172–83.
doi: 10.1016/j.clpt.2003.10.008
Paine MF, Khalighi M, Fisher JM, Shen DD, Kunze KL, Marsh CL, et al. Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. J Pharmacol Exp Ther. 1997;283(3):1552–62.
pubmed: 9400033
Oda Y, Kharasch ED. Metabolism of methadone and levo-alpha-acetylmethadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4): potential contribution of intestinal metabolism to presystemic clearance and bioactivation. J Pharmacol Exp Ther. 2001;298(3):1021–32.
pubmed: 11504799
Alfaro CL, Lam YW, Simpson J, Ereshefsky L. CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: intraindividual variability and plasma concentration correlations. J Clin Pharmacol. 2000;40(1):58–66.
pubmed: 10631623
doi: 10.1177/009127000004000108
Victorri-Vigneau C, Verstuyft C, Bouquie R, Laforgue EJ, Hardouin JB, Leboucher J, et al. Relevance of CYP2B6 and CYP2D6 genotypes to methadone pharmacokinetics and response in the OPAL study. Br J Clin Pharmacol. 2019;85(7):1538–43.
pubmed: 30907440
pmcid: 6595468
doi: 10.1111/bcp.13936
Taylor CP, Traynelis SF, Siffert J, Pope LE, Matsumoto RR. Pharmacology of dextromethorphan: relevance to dextromethorphan/quinidine (Nuedexta®) clinical use. Pharmacol Ther. 2016;164:170–82.
pubmed: 27139517
doi: 10.1016/j.pharmthera.2016.04.010
Galetin A, Clarke SE, Houston JB. Quinidine and haloperidol as modifiers of CYP3A4 activity: multisite kinetic model approach. Drug Metab Dispos. 2002;30(12):1512–22.
pubmed: 12433827
doi: 10.1124/dmd.30.12.1512
Kharasch ED, Bedynek PS, Hoffer C, Walker A, Whittington D. Lack of indinavir effects on methadone disposition despite inhibition of hepatic and intestinal cytochrome P4503A (CYP3A). Anesthesiology. 2012;116(2):432–47.
pubmed: 22273859
doi: 10.1097/ALN.0b013e3182423478
Totah RA, Allen KE, Sheffels P, Whittington D, Kharasch ED. Enantiomeric metabolic interactions and stereoselective human methadone metabolism. J Pharmacol Exp Ther. 2007;321(1):389–99.
pubmed: 17259447
doi: 10.1124/jpet.106.117580
Kharasch ED, Stubbert K. Role of cytochrome P4502B6 in methadone metabolism and clearance. J Clin Pharmacol. 2013;53(3):305–13.
pubmed: 23361846
pmcid: 3743098
doi: 10.1002/jcph.1
Wang SC, Ho IK, Tsou HH, Tian JN, Hsiao CF, Chen CH, et al. CYP2B6 polymorphisms influence the plasma concentration and clearance of the methadone S-enantiomer. J Clin Psychopharmacol. 2011;31(4):463–9.
pubmed: 21694616
doi: 10.1097/JCP.0b013e318222b5dd
Gadel S, Friedel C, Kharasch ED. Differences in methadone metabolism by CYP2B6 variants. Drug Metab Dispos. 2015;43(7):994–1001.
pubmed: 25897175
pmcid: 4468442
doi: 10.1124/dmd.115.064352
Kharasch ED, Regina KJ, Blood J, Friedel C. Methadone pharmacogenetics: CYP2B6 polymorphisms determine plasma concentrations, clearance, and metabolism. Anesthesiology. 2015;123(5):1142–53.
pubmed: 26389554
doi: 10.1097/ALN.0000000000000867
Brosseau N, Ramotar D. The human organic cation transporter OCT1 and its role as a target for drug responses. Drug Metab Rev. 2019;51(4):389–407.
pubmed: 31564168
doi: 10.1080/03602532.2019.1670204
Ferri N, Colombo E, Tenconi M, Baldessin L, Corsini A. Drug–drug interactions of direct oral anticoagulants (DOACs): from pharmacological to clinical practice. Pharmaceutics. 2022;14(6):1120.
pubmed: 35745692
pmcid: 9229376
doi: 10.3390/pharmaceutics14061120
Zahari Z, Lee CS, Ibrahim MA, Musa N, Mohd Yasin MA, Lee YY, et al. Relationship between ABCB1 polymorphisms and serum methadone concentration in patients undergoing methadone maintenance therapy (MMT). Am J Drug Alcohol Abuse. 2016;42(5):587–96.
pubmed: 27284701
doi: 10.3109/00952990.2016.1172078