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Comparison of Pharmacokinetic Profiles of
Brand-Name and Generic Formulations of Citalopram and Venlafaxine: A Crossover Study
Background: Generic drugs are lower-cost versions of patent-expired brand-name medications. Bioequivalence is decreed when the 90% confidence intervals for the ratios of the generic to the reference compound for the area under the curve and maximum plasma concentration (Cmax) fall within a 0.80 to 1.25 range. The aim of the present pilot study was to compare the pharmacokinetic profiles of brand-name and generic formulations of citalopram and extended-release venlafaxine.
Method: Effexor XR/Novo-venlafaxine XR 75 mg and Celexa/Gen-citalopram 40 mg were studied in a randomized crossover design. Healthy male volunteers took either Effexor XR or Novo-venlafaxine XR for 4 days, a 4-day washout was allowed, and then participants took the other venlafaxine formulation for 4 days. This was followed by a washout of at least 7 days. The participants then took Celexa or Gen-citalopram for 8 days, a 14-day washout was allowed, and then participants took the other citalopram formulation for 8 days. In each of the study phases, the sequence of treatment (brand-name × generic) was randomly assigned. Plasma levels of drugs were measured at fixed intervals after participants took the drugs and at steady state. The study was conducted from November 2007 through July 2008.
Results: Twelve participants completed the venlafaxine study. Nine of the participants, plus 3 new participants, were then enrolled in the citalopram study, to maintain a total of 12. The plasma levels of citalopram were similar after ingestion of the brand-name and generic drugs. After ingestion of venlafaxine, the Cmax values were 36 ± 6 ng/mL and 52 ± 8 ng/mL in the brand-name and generic groups, respectively. The ratio of the log-transformed values of Cmax was 150% and, therefore, not within the acceptable 80% to 125% range. The concentration of the active metabolite of venlafaxine (O-desmethyl-venlafaxine [ODV]) was also significantly increased in the generic group (+43% higher in the generic group at 3 h; +48% higher at 5 h; p < .05). No differences were seen at steady state for either ODV or venlafaxine. Participants taking Novo-venlafaxine reported 3 times more side effects than those taking Effexor XR. Pill contents were identical in the 2 groups, but extraction of venlafaxine occurred more readily with the generic formulation than with the brand-name formulation, which required an additional sonication.
Conclusion: Gen-citalopram appeared to be bioequivalent to Celexa, whereas Novo-venlafaxine XR was not bioequivalent to Effexor XR. Consequently, the Novo-venlafaxine formulation released its active ingredient more rapidly and outside the acceptable norm.
Trial Registration: clinicaltrials.gov Identifier: NCT00676039
J Clin Psychiatry 2009:70(7);958–966. doi:10.4088/JCP.09m05315
© Copyright 2009 Physicians Postgraduate Press, Inc.
Received April 28, 2009; accepted May 1, 2009. From the Institute of Mental Health Research (Drs. Chenu and Blier and Mss. Batten and Hébert) and Department of Cellular and Molecular Medicine (Dr. Blier) University of Ottawa, Ontario, Canada; and Experimental Psychiatry Unit, Department of General Psychiatry and Social Psychiatry, Medical University Innsbruck, Austria (Dr. Zernig and Ms. Ladstaetter).
Funding for this work was received in the form of unrestricted grants from AstraZeneca, Biovail, Organon, and Wyeth; salary support from the Institute of Mental Health Research, University of Ottawa, to Drs. Chenu and Blier and Mss. Batten and Hébert and a Research Chair in Psychopharmacology from the Canadian Government to Dr. Blier. Liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis of medication levels was supported by the Verein für Experimentelle Psychiatrie, Psychotherapie und Pharmakologie, Innsbruck, Austria.
Dr. Blier has received honoraria for consultancy and speaking engagements to and has produced, under contract, educational materials for Lundbeck and Wyeth; has been a consultant to Biovail, Eli Lilly, Forest, Janssen, Organon, Sepracor, Sanofi-Aventis, Pfizer, Novartis, Takeda, and Bristol-Myers Squibb; has served on speakers bureaus for Cyberonics, Eli Lilly, Forest, Janssen, Lundbeck, Organon, and Wyeth-Ayerst; has received grant funding from Eli Lilly, Forest, Janssen, Lundbeck, Mitsubishi Pharma, Organon, Wyeth-Ayerst, and Bristol-Myers Squibb; has been a contract employee of Forest, Janssen, Steelbeach Productions, and Bristol-Myers Squibb; and is president of Medical Multimedia. Drs. Chenu and Zernig and Mss. Batten, Ladstaetter, and Hébert report no additional financial or other relationships relevant to the subject of the article.
Corresponding author and reprints: Franck Chenu, Pharm.D., Ph.D., Institute of Mental Health Research, 1145 Carling Ave., University of Ottawa, Ottawa, K1Z 7K4 Ontario, Canada (e-mail: franck.chenu@rohcg.on.ca).