Stereoselective Steady-State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults.
Administration, Oral
Adult
Antidepressive Agents, Second-Generation
/ administration & dosage
Biotransformation
Bupropion
/ administration & dosage
Cross-Over Studies
Depressive Disorder, Major
/ diagnosis
Double-Blind Method
Drugs, Generic
/ administration & dosage
Female
Humans
Male
Middle Aged
Prospective Studies
Renal Elimination
Stereoisomerism
Therapeutic Equivalency
Journal
Clinical pharmacology and therapeutics
ISSN: 1532-6535
Titre abrégé: Clin Pharmacol Ther
Pays: United States
ID NLM: 0372741
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
04
02
2020
accepted:
20
04
2020
pubmed:
10
5
2020
medline:
26
5
2021
entrez:
10
5
2020
Statut:
ppublish
Résumé
The antidepressant bupropion is stereoselectively metabolized and metabolite enantiomers have differential pharmacologic effects, but steady-state enantiomeric disposition is unknown. Controversy persists about bupropion XL 300 mg generic equivalence to brand product, and whether generics might have different stereoselective disposition leading to enantiomeric non-bioequivalence and, thus, clinical nonequivalence. This preplanned follow-on analysis of a prospective, randomized, double-blinded, crossover study of brand and 3 generic bupropion XL 300 mg products measured steady-state enantiomeric plasma and urine parent bupropion and primary and secondary metabolite concentrations and evaluated bioequivalence and pharmacokinetics. Steady-state plasma and urine bupropion disposition was markedly stereoselective, with up to 40-fold differences in plasma concentrations of the active metabolite S,S-hydroxybupropion vs. R,R,-hydroxybupropion. Urine metabolite glucuronides were prominent, but glucuronidation was metabolite-specific and enantioselective. There were no differences between any generic and brand, or between generics, in plasma enantiomer concentrations of bupropion or the major metabolites. All generic products satisfied formal bioequivalence criteria (peak plasma concentration (C
Substances chimiques
Antidepressive Agents, Second-Generation
0
Drugs, Generic
0
Bupropion
01ZG3TPX31
Types de publication
Comparative Study
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1036-1048Informations de copyright
© 2020 The Authors. Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.
Références
Patel, K., Allen, S., Haque, M.N., Angelescu, I., Baumeister, D. & Tracy, D.K. Bupropion: a systematic review and meta-analysis of effectiveness as an antidepressant. Ther. Adv. Psychopharmacol. 6, 99-144 (2016).
Reid, R.D., Pritchard, G., Walker, K., Aitken, D., Mullen, K.A. & Pipe, A.L. Managing smoking cessation. CMAJ 188, E484-E492 (2016).
Wilding, J.P. Combination therapy for obesity. J. Psychopharmacol. 31, 1503-1508 (2017).
Verbeeck, W., Bekkering, G.E., Van den Noortgate, W. & Kramers, C. Bupropion for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database Syst. Rev. 10, CD009504 (2017).
Cools, O. et al. Pharmacotherapy and nutritional supplements for seasonal affective disorders: a systematic review. Expert Opin. Pharmacother. 19, 1221-1233 (2018).
Lee, N.K., Jenner, L., Harney, A. & Cameron, J. Pharmacotherapy for amphetamine dependence: a systematic review. Drug Alcohol Depend. 191, 309-337 (2018).
Chan, B., Kondo, K., Freeman, M., Ayers, C., Montgomery, J. & Kansagara, D. Pharmacotherapy for cocaine use disorder-a systematic review and meta-analysis. J. Gen. Intern. Med. 34, 2858-2873 (2019).
Urits, I. et al. Off-label antidepressant use for treatment and management of chronic pain: evolving understanding and comprehensive review. Curr. Pain Headache Rep. 23, 66 (2019).
Johnston, A.J. et al. Pharmacokinetic optimisation of sustained-release bupropion for smoking cessation. Drugs 62 (suppl. 2), 11-24 (2002).
Lee, A.M. et al. CYP2B6 genotype alters abstinence rates in a bupropion smoking cessation trial. Biol. Psychiatry 62, 635-641 (2007).
Zhu, A.Z. et al. CYP2B6 and bupropion's smoking-cessation pharmacology: the role of hydroxybupropion. Clin. Pharmacol. Ther. 92, 771-777 (2012).
Laib, A.K., Brunen, S., Pfeifer, P., Vincent, P. & Hiemke, C. Serum concentrations of hydroxybupropion for dose optimization of depressed patients treated with bupropion. Ther. Drug Monit. 36, 473-479 (2014).
Malcolm, E., Carroll, F.I., Blough, B., Damaj, M.I. & Shoaib, M. Examination of the metabolite hydroxybupropion in the reinforcing and aversive stimulus effects of nicotine in rats. Psychopharmacology 232, 2763-2771 (2015).
Cremers, T.I., Flik, G., Folgering, J.H., Rollema, H. & Stratford, R.E. Jr. Development of a rat plasma and brain extracellular fluid pharmacokinetic model for bupropion and hydroxybupropion based on microdialysis sampling, and application to predict human brain concentrations. Drug Metab. Dispos. 44, 624-633 (2016).
GlaxoSmithKline (GSK) reviews novel therapeutics for CNS disorders and confirms strong pipeline momentum (Press Release, 11/23/2004) <https://web.archive.org/web/20070928041150/http://www.biospace.com/news_story.aspx?StoryID=18222420&full=1> (2004). Accessed August 27, 2018.
Coles, R. & Kharasch, E.D. Stereoselective metabolism of bupropion by CYP2B6 and human liver microsomes. Pharm. Res. 25, 1405-1411 (2008).
Sager, J.E., Price, L.S. & Isoherranen, N. Stereoselective metabolism of bupropion to OH-bupropion, threohydrobupropion, erythrohydrobupropion, and 4'-OH-bupropion in vitro. Drug Metab. Dispos. 44, 1709-1719 (2016).
Gufford, B.T., Lu, J.B., Metzger, I.F., Jones, D.R. & Desta, Z. Stereoselective glucuronidation of bupropion metabolites in vitro and in vivo. Drug Metab. Dispos. 44, 544-553 (2016).
Coles, R. & Kharasch, E.D. Stereoselective analysis of bupropion and hydroxybupropion in human plasma and urine by LC/MS/MS. J. Chromatogr. B 857, 67-75 (2007).
Kharasch, E.D., Mitchell, D. & Coles, R. Stereoselective bupropion hydroxylation as an in vivo phenotypic probe for cytochrome P4502B6 (CYP2B6) activity. J. Clin. Pharmacol. 48, 464-474 (2008).
Masters, A.R., Gufford, B.T., Lu, J.B., Metzger, I.F., Jones, D.R. & Desta, Z. Chiral plasma pharmacokinetics and urinary excretion of bupropion and metabolites in healthy volunteers. J. Pharmacol. Exp. Ther. 358, 230-238 (2016).
Teitelbaum, A.M., Flaker, A.M. & Kharasch, E.D. Development, validation and application of a comprehensive stereoselective LC/MS-MS assay for bupropion and oxidative, reductive, and glucuronide metabolites in human urine. J. Chromatogr. B 1027, 239-253 (2016).
Teitelbaum, A.M., Flaker, A.M. & Kharasch, E.D. Development and validation of a high-throughput stereoselective LC-MS/MS assay for bupropion, hydroxybupropion, erythrohydrobupropion, and threohydrobupropion in human plasma. J. Chromatogr. B 1017-1018, 101-113 (2016).
Kharasch, E.D. & Crafford, A. Common polymorphisms of CYP2B6 influence stereoselective bupropion disposition. Clin. Pharmacol. Ther. 105, 142-152 (2019).
Kharasch, E.D., Mitchell, D., Coles, R. & Blanco, R. Rapid clinical induction of hepatic cytochrome P4502B6 activity by ritonavir. Antimicrob. Agents Chemother. 52, 1663-1669 (2008).
Bondarev, M.L., Bondareva, T.S., Young, R. & Glennon, R.A. Behavioral and biochemical investigations of bupropion metabolites. Eur. J. Pharmacol. 474, 85-93 (2003).
Damaj, M.I. et al. Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors. Mol. Pharmacol. 66, 675-682 (2004).
Damaj, M.I. et al. Effects of hydroxymetabolites of bupropion on nicotine dependence behavior in mice. J. Pharmacol. Exp. Ther. 334, 1087-1095 (2010).
Lukas, R.J. et al. Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation. J. Med. Chem. 53, 4731-4748 (2010).
Sager, J.E., Choiniere, J.R., Chang, J., Stephenson-Famy, A., Nelson, W.L. & Isoherranen, N. Identification and structural characterization of three new metabolites of bupropion in humans. ACS Med. Chem. Lett. 7, 791-796 (2016).
Connarn, J.N. et al. Identification of non-reported bupropion metabolites in human plasma. Biopharm. Drug Dispos. 37, 550-560 (2016).
Review of therapeutic equivalence generic Bupropion XL 300 mg and Wellbutrin XL 300 mg. US Food and Drug Administration (FDA), archived at: <https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm153270.htmhttps://wayback.archive-it.org/7993/20171102213516/> (2012).
Update: Budeprion XL 300 mg not therapeutically equivalent to Wellbutrin XL 300 mg. Food and Drug Administration (FDA), Center for Drug Evaluation and Research <http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm322161> (2012).
Woodcock, J., Khan, M. & Yu, L.X. Withdrawal of generic budeprion for nonbioequivalence. N. Engl. J. Med. 367, 2463-2465 (2012).
Kharasch, E.D. et al. Bioequivalence and therapeutic equivalence of generic and brand bupropion in adults with major depression: A randomized clinical trial. Clin. Pharmacol. Ther. 105, 1164-1174 (2019).
US Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry: Statistical approaches to establishing bioequivalence <https://www.fda.gov/downloads/Drugs/Guidances/ucm070244.pdf> (2001).
Food and Drug Administration, Center for Drug Evaluation and Research, U.S. Department of Health and Human Services. Guidance for industry: Bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an ANDA <https://www.fda.gov/downloads/drugs/guidances/ucm377465.pdf> (2013).
US Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry: Bioavailability and bioequivalence studies for orally administered drug products - General considerations <https://www.ipqpubs.com/wp-content/uploads/2014/04/BABEOld.pdf> (2003).
Endrenyi, L. & Tothfalusi, L. Metrics for the evaluation of bioequivalence of modified-release formulations. AAPS J. 14, 813-819 (2012).
Bate, R. et al. Generics substitution, bioequivalence standards, and international oversight: complex issues facing the FDA. Trends Pharmacol. Sci. 37, 184-191 (2016).
Benowitz, N.L., Zhu, A.Z., Tyndale, R.F., Dempsey, D. & Jacob, P. 3rd. Influence of CYP2B6 genetic variants on plasma and urine concentrations of bupropion and metabolites at steady state. Pharmacogenet. Genomics 23, 135-141 (2013).
Garcia-Arieta, A. et al. Investigation on the need of multiple dose bioequivalence studies for prolonged-release generic products. Int. J. Pharm. 423, 321-325 (2012).
Teitelbaum, A.M. & Kharasch, E.D. Misidentification of bupropion glucuronide metabolites and re-evaluation of metabolite pharmacokinetics. Drug Metab. Dispos. 44, 1851 (2016).
Association for Accessible Medicines. Generic drug and biosimilars access and savings <https://accessiblemeds.org/resources/reports/2019-access-and-savings-report> (2019). Accessed February 1, 2020.
Kesselheim, A.S. et al. Variations in patients' perceptions and use of generic drugs: Results of a national survey. J. Gen. Intern. Med. 31, 609-614 (2016).
Kesselheim, A.S. et al. Prevalence and predictors of generic drug skepticism among physicians: results of a national survey. JAMA Intern. Med. 176, 845-847 (2016).
Sharfstein, J.M. & Greene, J. Promise and peril for generic drugs. JAMA Intern. Med. 176, 733-734 (2016).
US Food and Drug Administration, Center for Drug Evaluation and Research. Update: Bupropion Hydrochloride extended-release 300 mg bioequivalence studies <https://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm322161.htm> (2013). Accessed August 27, 2018.