Background: A new tablet formulation of methadone was developed with unique physicochemical properties, allowing for decreased solubility in aqueous solutions in in vitro studies. It was unknown whether this newly developed formulation would affect its bioavailability compared with the currently available formulation of methadone.
Objectives: The objective of this study was to further examine the in vitro solubility of the new methadone formulation, and to evaluate and compare the relative bioavailability and pharmacokinetics to the previous reference formulation after a single oral dose administration under fasting conditions.
Methods: In vitro comparative dissolution for the new methadone formulation and the previous reference formulation was conducted. A randomized, single-dose, blinded, two-period, two-sequence, crossover pharmacokinetic study was performed in 24 healthy volunteers under fasting conditions.
Results: The new methadone formulation demonstrated a 30–40% decrease in solubility over 30 minutes compared with the previous reference formulation at the highest dose; all other doses also showed decreased in vitro solubility. The pharmacokinetic parameters determined were: maximum plasma drug concentration (Cmax) of 38.1 ng/mL; time to reach Cmax (tmax) of 2.80 hours; mean area under the plasma concentration-time curve (AUC) from time zero to 72 hours (AUC72) of 1043 ng • h/mL; mean AUC from time zero to infinity (AUC∞) of 1430 ng • h/mL; mean elimination rate constant (ke) of 0.0206 hours-1; and mean elimination half-life (t1/2) of 36.7 hours. These values are statistically equivalent to the previous reference formulation of methadone.
Conclusion: This study provides the first complete set of pharmacokinetic data on a novel methadone formulation. The formulation demonstrates decreased in vitro solubility while providing equivalent plasma methadone levels compared with the previous formulation.
References
Mercadante S, Casuccio A, Fulfaro F, et al. Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study. J Clin Oncol 2001; 19: 2898–904
Leppert W. The role of methadone in cancer pain treatment: a review. Int J Clin Pract 2009; 63: 1095–109
Nicholson AB. Methadone for cancer pain. Cochrane Database Syst Rev 2007; 17: CD003971
Mizoguchi H, Watanabe C, Yonezawa A, et al. New therapy for neuropathic pain. Int Rev Neurobiol 2009; 85: 249–60
Mannino R, Coyne P, Swainey C, et al. Methadone for cancer-related neuropathic pain: a review of the literature. J Opioid Manag 2006; 2: 269–76
Stotts AL, Dodrill CL, Kosten TR. Opioid dependence treatment: options in pharmacotherapy. Expert Opin Pharmacother 2009; 10: 1727–40
Kleber HD. Pharmacologic treatments for opioid dependence: detoxification and maintenance options. Dialogues Clin Neurosci 2007; 9: 455–70
Iribarne C, Berthou F, Baird S, et al. Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. Chem Res Toxicol 1996; 9: 365–73
Moody DE, Alburges ME, Parker RJ, et al. The involvement of cytochrome P450 3A4 in the N-demethylation of l-a-acetylmethadol (laam), norlaam, and methadone. Drug Metab Dispos 1997; 25: 1347–53
Davis MP, Walsh D. Methadone for relief of cancer pain: a review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration. Support Care Cancer 2001; 9: 73–83
Wang SC, Ho IK, Tsou HH, et al. CYP2B6 polymorphisms influence the plasma concentration and clearance of the methadone S-enantiomer. J Clin Psychopharmacol 2011; 31: 463–9
Bunten H, Liang WJ, Pounder D, et al. CYP2B6 and OPRM1 gene variations predict methadone-related deaths. Addict Biol 2011; 16: 142–4
Bruera E, Sweeney C. Methadone use in cancer patients with pain: a review. J Palliative Med 2002; 5: 127–38
Wolff K, Rostami-Hodjegan A, Shires S, et al. The pharmacokinetics of methadone in healthy subjects and opiate users. Br J Clin Pharmacol 1997; 44: 325–34
Foster DJ, Somogyi AA, White JM, et al. Population pharmacokinetics of (R)-, (S)- and rac-methadone in methadone maintenance patients. Br J Clin Pharmacol 2004; 57: 742–55
Plummer JL, Gourlay GK, Cherry DA, et al. Estimation of methadone clearance: application in the management of cancer pain. Pain 1988; 33: 313–22
Metadol® (methadone hydrochloride): Canadian Product Monograph. Montreal: Paladin Labs Inc., 2003
Lynch ME. A review of the use of methadone for the treatment of chronic noncancer pain. Pain Res Manage 2005; 10: 133–44
Betancourt AO, Gosselin, PM, Vinson RK. New immediate release formulation for deterring abuse of methadone. Pharmaceutical Development and Technology. Epub 2012 Apr 27 DOI: 10.3109/10837450.2012.680598
United States Pharmacopeia/National Formulary February 1, 2011 [online]. Available from URL: http://www.uspnf.com [Accessed 2011 Apr 18]
Webster L. Update on abuse-resistant and abuse-deterrent approaches to opioid formulations. Pain Med 2009; 10: S124–33
Raffa RB, Pergolizzi JV. Opioid formulations designed to resist/deter abuse. Drugs 2010; 70: 1657–75
Gourevitch MN, Hartel D, Tenore P, et al. Three oral formulations of methadone: a clinical and pharmacodynamic comparison. J Subst Abuse Treat 1999; 17: 237–41
Dale O, Hoffer C, Sheffels P, et al. Disposition of nasal, intravenous, and oral methadone in healthy volunteers. Clin Pharmacol Ther 2002; 72: 536–45
Inturrisi CE, Verebely K. Disposition of methadone in man after a single oral dose. Clin Pharmacol Ther 1972; 13: 923–30
Kukanich B, Lascelles BD, Aman AM, et al. The effects of inhibiting cytochrome P450 3A, p-glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs. J Vet Pharmacol Ther 2005; 28: 461–6
Silver JS, Shaffer HJ. Change intolerance to shifts in methadone formulation: a preliminary investigation. J Subst Abuse Treat 1996; 13: 331–9
Steels MD, Hamilton M, McLean PC. The consequences of a change in formulation of methadone prescribed in a drug clinic. Br J Addict 1992; 87: 1549–54
Acknowledgements
R.K. Vinson was responsible for the design and interpretation of the study, and preparation of the manuscript. All work described in this manuscript was funded by Paladin Labs Inc., Montreal, Canada. R.K. Vinson is an employee of Paladin Labs Inc.
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Vinson, R.K. Pharmacokinetics of a New Immediate-Release Methadone Tablet Formulation with Decreased In vitro Solubility. Clin Drug Investig 32, 487–495 (2012). https://doi.org/10.2165/11633550-000000000-00000
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DOI: https://doi.org/10.2165/11633550-000000000-00000