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Evaluation of Cytochrome P450 (CYP) 3A4-Based Interactions of Levomilnacipran with Ketoconazole, Carbamazepine or Alprazolam in Healthy Subjects

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Abstract

Background and Objectives

Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor with balanced potency for the reuptake inhibition of norepinephrine and serotonin, approved in the USA for the treatment of major depressive disorder (MDD) in adults. We conducted studies in healthy human subjects to investigate pharmacokinetic interactions when levomilnacipran extended-release (ER) is administered in combination with an inhibitor (ketoconazole), an inducer (carbamazepine), or a substrate (alprazolam) of cytochrome P450 (CYP) 3A4.

Methods

Randomised, open-label studies were conducted in healthy volunteers (n = 34 ketoconazole, n = 34 carbamazepine, n = 30 alprazolam) and pharmacokinetic parameters were determined when levomilnacipran was administered alone or together with the relevant study drug.

Results

Co-administration of ketoconazole with levomilnacipran ER increased levomilnacipran maximum concentration (C max) by 39 % [90 % confidence interval (CI) 31–47 %] and area under the concentration–time curve (AUC) by 57 % (90 % CI 47–67 %), whereas carbamazepine reduced the C max and AUC of levomilnacipran by 26 % (90 % CI 22–30 %) and 29 % (90 % CI 26–32 %), respectively. Levomilnacipran at steady state had no significant effect on the pharmacokinetics of a single 1 mg dose of alprazolam extended release (XR); neither did single-dose alprazolam XR affect the steady-state pharmacokinetics of levomilnacipran. No new safety concerns were noted in these studies.

Conclusions

Based on these results, the levomilnacipran ER dose should not exceed 80 mg once daily when used with ketoconazole, compared to 120 mg once daily in the absence of ketoconazole. No dose adjustment for levomilnacipran is suggested when levomilnacipran ER is co-administered with carbamazepine or other CYP3A4 inducers. Co-administration with levomilnacipran of drugs metabolised by CYP3A4, such as alprazolam, requires no dose adjustment due to pharmacokinetic considerations.

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Acknowledgments

We thank Hao Chen (Forest Research Institute, Inc., NY) and Valerie Brunner (Pierre Fabre Médicament, Toulouse, France) for their work on the in vitro studies that preceded this work.

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Authors and Affiliations

  1. Forest Research Institute, Inc., an affiliate of Actavis Inc., Harborside Financial Center, Plaza V, Jersey City, NJ, 07311, USA

    Laishun Chen, Ramesh Boinpally & Antonia Periclou

  2. Union City, NJ, USA

    Nayra Gad

  3. Mental Health Association of Rockland County, Valley Cottage, NY, USA

    William M. Greenberg

  4. Smithtown, NY, USA

    Julie Wangsa

  5. Weehawken, NJ, USA

    Parviz Ghahramani

Authors
  1. Laishun Chen
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  2. Ramesh Boinpally
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  3. Nayra Gad
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  4. William M. Greenberg
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  5. Julie Wangsa
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  6. Antonia Periclou
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  7. Parviz Ghahramani
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Corresponding author

Correspondence to Laishun Chen.

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Funding

These studies were supported by funding from Forest Research Institute, Inc., an affiliate of Actavis, Inc. (New York, NY), and Pierre Fabre Médicament, Boulogne, France. Both companies were involved in the study design, collection (via contracted clinical investigator sites), analysis and interpretation of data, and the decision to present these results.

Writing assistance, editorial, and logistical support for this manuscript was provided by Grace Townshend and Daria Renshaw of Watermeadow Medical, UK, and funded by Forest Research Institute, Inc.

Conflicts of interest

LC, RB and AP are all employees of Forest Research Institute, Inc., an affiliate of Actavis, Inc.

LC, RB and AP hold stock/stock options in Actavis, Inc.

WMG, NG, JW and PG were employees of Forest Research Institute, Inc., at the time of these studies. WMG held stock/stock options in Forest Research Institute, Inc. while an employee, but no longer holds them.

Ethical approval

All procedures in the three studies were in accordance with the 1964 Helsinki Declaration (and its amendments), and the Ethical Committee or institutional review board that approved the study.

Informed consent

Written informed consent was obtained from all subjects.

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Chen, L., Boinpally, R., Gad, N. et al. Evaluation of Cytochrome P450 (CYP) 3A4-Based Interactions of Levomilnacipran with Ketoconazole, Carbamazepine or Alprazolam in Healthy Subjects. Clin Drug Investig 35, 601–612 (2015). https://doi.org/10.1007/s40261-015-0318-2

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  • DOI: https://doi.org/10.1007/s40261-015-0318-2

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