Abstract
Rationale
Two biomarkers: concentration ratio of O-desmethylvenlafaxine/venlafaxine and concentration sum of venlafaxine + O-desmethylvenlafaxine were adopted to indicate venlafaxine responses, but neither is validated.
Objectives
To evaluate the ability of two biomarkers in reflecting venlafaxine pharmacokinetic variations, and to further examine their relationship with venlafaxine treatment outcomes.
Methods
Two well-defined influencing factors: CYP2D6 genotypes and drug interactions were enriched into a three-period crossover study to produce venlafaxine pharmacokinetic variations: In each period, healthy CYP2D6 extensive metabolizers (EM group; n = 12) and CYP2D6*10/*10 intermediate metabolizers (IM group; n = 12) were pretreated with clarithromycin (CYP3A4 inhibitor), or nothing (control), or clarithromycin + paroxetine (CYP3A4 + CYP2D6 inhibitors), before administration of a single-dose of 75 mg venlafaxine. Both biomarkers were evaluated (1) for their relationship with the influencing factors in healthy volunteers and (2) for their relationships with the venlafaxine responses/adverse events reported in two patient studies.
Results
Significant venlafaxine pharmacokinetic variations were observed between the EM and IM groups (geometric mean ratio [95 % CI] of area under the curve, 3.0 [1.8–5.1] in the control period), and between the control and clarithromycin + paroxetine periods (4.1 [3.5–4.7] and 2.0 [1.7–2.4] in the EM and IM group, respectively). O-Desmethylvenlafaxine/venlafaxine was superior to venlafaxine + O-desmethylvenlafaxine to reflect the influencing factors. In the patient studies, O-desmethylvenlafaxine/venlafaxine > 4 showed high precision in predicting venlafaxine responders/partial-responders (92 %) and patients without venlafaxine-related adverse events (88 %); the O-desmethylvenlafaxine/venlafaxine < 4 and venlafaxine + O-desmethylvenlafaxine > 400 ng/ml combination showed higher precision (100 %) than O-desmethylvenlafaxine/venlafaxine < 4 alone (65 %) in predicting venlafaxine non-responders.
Conclusion
We propose using O-desmethylvenlafaxine/venlafaxine for CYP2D6 phenotyping, and O-desmethylvenlafaxine/venlafaxine with venlafaxine + O-desmethylvenlafaxine for predicting venlafaxine treatment outcomes in future prospective studies.
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Acknowledgments
This research was supported by a grant (11181MFDS655) from Ministry of Food and Drug Safety in 2011.
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Hae-Deun Kim and Fen Jiang have contributed equally to this article.
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Jiang, F., Kim, HD., Na, HS. et al. The influences of CYP2D6 genotypes and drug interactions on the pharmacokinetics of venlafaxine: exploring predictive biomarkers for treatment outcomes. Psychopharmacology 232, 1899–1909 (2015). https://doi.org/10.1007/s00213-014-3825-6
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DOI: https://doi.org/10.1007/s00213-014-3825-6