Bioequivalence and Bioinequivalence of Two Original Antidepressant Medications and Their Generics

Franck Chenu, PharmD, PhD; Lisa Batten, MA; Gerald Zernig, MD; Elisabeth Ladstaetter, MTA; Chantal Hebert, RN; and Pierre Blier, MD, PhD
The University of Ottawa, Ontario, Canada (Drs Blier and Chenu, Ms Batten, and Ms Hebert); and the Medical University, Innsbruck, Austria (Dr Zernig and Ms Ladstaetter)

This poster presentation was supported by Wyeth, Organon, Biovail, and AstraZeneca.

Background: Generic drugs are lower-cost versions of patent-expired original brand name medications.¹ Bioequivalence is established when the 90% confidence interval (CI) of the ratio of the generic to the reference compound for the area-under-the-curve and maximum plasma concentration (Cmax) fall within 80–125% range. A previous report described a high rate of relapse in patients switched from brand to generic formulation of citalopram (CIT),² and similar cases were observed in Canada since the introduction of generic venlafaxine (VEN). The aim of the present study was to compare the pharmacokinetic profile of original and generic formulations of venlafaxine and citalopram in 12 healthy volunteers.

Methods: Effexor/Novo-venlafaxine (TEVA) XR 75 mg and Celexa/Gen-citalopram 40 mg were studied in a randomized cross-over design. Plasma levels of drugs were measured at fixed intervals after taking the drugs (CIT: one to three hours; VEN: two to six hours), as well as at steady state (CIT: day 8; VEN: day 5).

Results: The plasma levels of CIT were similar after the ingestion of the brand and the generic drug. After ingestion of VEN, the Cmax were 36±6 and 52±8 ng/mL in the brand and generic groups, respectively. The ratio of the log-transformed values of Cmax was of 150%, the corresponding 90% CI was of 104%–217% and therefore was not within the acceptable 80% to 125% range. The concentration of the active metabolite of VEN (O-Desmethylvenlafaxine, ODV) was also significantly increased in the generic group (+43–48% at 3, 4, 5 and 6 hours). No differences were obtained at steady state for both the ODV and VEN. Subjects under generic medication reported three times more side effects than those taken the brand-name medication. Pill contents were the same in the two groups, but the extraction of the generic occurred more readily than the brand which required an additional sonication.

Conclusions: Gen-citalopram appeared to be bio-equivalent to Celexa, whereas Novo-venlafaxine was not bioequivalent to Effexor. Consequently, the Novo-venlafaxine formulation was releasing its active ingredient more rapidly and outside of the prescribed norm.

References

1. Borgheini G. The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin Ther. 2003;25(6):1578–1592.
2. Van Ameringen M, Mancini C, Patterson B, et al. Symptom relapse following switch from Celexa to generic citalopram: an anxiety disorders case series. J Psychopharmacol. 2007;21(5):472–476.

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