Bioequivalence and Therapeutic Equivalence of Generic and Brand Bupropion in Adults With Major Depression: A Randomized Clinical Trial

Kharasch, Evan D.; Neiner, Alicia; Kraus, Kristin; Blood, Jane; Stevens, Angela; Schweiger, Julia; Miller, J. Philip; Lenze, Eric J.

doi:10.1002/cpt.1309

Cited by 15 publications

(23 citation statements)

References 34 publications

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“…In addition to testing for sameness (bioequivalence), parameters were also analyzed for differences. 35 No significant differences were found ( Supplementary Table S1). Additional plasma pharmacokinetic parameters (bupropion total apparent clearance, bupropion and metabolite apparent half-life, and metabolite/parent ratios) were generally comparable between generics and brand bupropion, and between generics ( Table 2).…”

Section: Stereospecific Bioequivalence Of Generic Bupropionmentioning

confidence: 98%

“…[32][33][34] Thus, we evaluated the bioequivalence of steady-state extended release bupropion XL 300 mg, for brand and 3 generic products, using standard plasma pharmacokinetic parameters for bupropion and the 3 major metabolites hydroxybupropion, erythrohydrobupropion, and threohydrobupropion. 35 We reported bioequivalence among all products; however, this was for achiral (racemic) results, and for plasma only. Given the differences in bupropion metabolite enantiomer effects, understanding the bioequivalence of brand and generic enantiomers was important.…”

mentioning

confidence: 89%

“…This investigation is a follow-up analysis of a prospective, randomized, double-blinded, 4-period, balanced, single-center crossover study comparing bioequivalence and therapeutic equivalence of 3 bupropion XL 300 mg generics to brand Wellbutrin XL 300 mg bupropion (clinicaltrials.gov, NCT02209597). 35 It was approved by the Washington University Institutional Review Board and the US Food and Drug Administration (FDA) Research Involving Human Subjects Committee. All subjects provided written, informed consent.…”

Section: Protocolmentioning

confidence: 99%

“…As reported previously, the study cohort (n = 70) was (median, interquartile range) 47 years (37-57), 76 kg (63-94), and body mass index 26 (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33), with 53 women (76%), and 64 whites, 5 African Americans, and 1 Asian. 35 Pharmacokinetic evaluations were performed 10-20 days after starting each drug product to allow for steady-state. Pharmacokinetic data are presented for all patients (n = 70).…”

Section: Patient Characteristicsmentioning

confidence: 99%

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Stereoselective Steady‐State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults

Kharasch

Neiner

Kraus

et al. 2020

Clin Pharma and Therapeutics

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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 max) and area under the plasma concentration-time curve over 24 hours (AUC 0-24)) using enantiomers for bupropion as well as for metabolites, and generics were comparable to each other, and were considered bioequivalent, based on enantiomeric analysis. Enantiomeric bioequivalence explains the previously observed therapeutic equivalence of bupropion generics and brand in treating major depression. These results have important implications for understanding the clinical therapeutic effects of bupropion based on complex and stereoselective metabolism.

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Section: Stereospecific Bioequivalence Of Generic Bupropionmentioning

confidence: 98%

mentioning

confidence: 89%

Section: Protocolmentioning

confidence: 99%

Section: Patient Characteristicsmentioning

confidence: 99%

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Stereoselective Steady‐State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults

Kharasch

Neiner

Kraus

et al. 2020

Clin Pharma and Therapeutics

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“…In brief, methadone was from the National Institute on Drug Abuse (Bethesda, MD); all other reagents were purchased from Sigma‐Aldrich. Reactions were quenched with 40 μl 20% trichloroacetic acid containing internal standard (d3‐EDDP), and centrifuged for 5 minutes at 2500 g ; the supernatant was processed by solid phase extraction as previously described, except that for Strata‐X‐C 33‐μm, 30 mg/well plates (Phenomenex, Torrance, CA) were used. Analysis was performed on a Sunfire C18 column (2.1 × 50 mm, 3.5‐μm) (Waters, Milford, MA) with a 2‐μm column filter guard (Supleco Analytical, Bellefonte, PA).…”

Section: Methodsmentioning

confidence: 99%

Nicotine oxidation by genetic variants of CYP2B6 and in human brain microsomes

Bloom

Wang

Kharasch

2019

Pharmacology Res & Perspec

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Common variation in the CYP 2B6 gene, encoding the cytochrome P450 2B6 enzyme, is associated with substrate‐specific altered clearance of multiple drugs. CYP 2B6 is a minor contributor to hepatic nicotine metabolism, but the enzyme has been proposed as relevant to nicotine‐related behaviors because of reported CYP 2B6 mRNA expression in human brain tissue. Therefore, we hypothesized that CYP 2B6 variants would be associated with altered nicotine oxidation, and that nicotine metabolism by CYP 2B6 would be detected in human brain microsomes. We generated recombinant enzymes in insect cells corresponding to nine common CYP 2B6 haplotypes and demonstrate genetically determined differences in nicotine oxidation to nicotine iminium ion and nornicotine for both (S) and (R)‐nicotine. Notably, the CYP 2B6.6 and CYP 2B6.9 variants demonstrated lower intrinsic clearance relative to the reference enzyme, CYP 2B6.1. In the presence of human brain microsomes, along with nicotine‐ N ‐oxidation, we also detect nicotine oxidation to nicotine iminium ion. However, unlike N ‐oxidation, this activity is NADPH independent, does not follow Michaelis‐Menten kinetics, and is not inhibited by NADP or carbon monoxide. Furthermore, metabolism of common CYP 2B6 probe substrates, methadone and ketamine, is not detected in the presence of brain microsomes. We conclude that CYP 2B6 metabolizes nicotine stereoselectively and common CYP 2B6 variants differ in nicotine metabolism activity, but did not find evidence of CYP 2B6 activity in human brain.

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Prescribing Antidepressant Medication

Kroll

2022

Caring for Patients With Depression in Primary Care

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Bioequivalence and Therapeutic Equivalence of Generic and Brand Bupropion in Adults With Major Depression: A Randomized Clinical Trial

Cited by 15 publications

References 34 publications

Stereoselective Steady‐State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults

Stereoselective Steady‐State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults

Nicotine oxidation by genetic variants of CYP2B6 and in human brain microsomes

Prescribing Antidepressant Medication

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