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The Impact of Sertraline Co-Administration on the Pharmacokinetics of Olanzapine: A Population Pharmacokinetic Analysis of the STOP-PD

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Abstract

Background and Objective

Clinical evidence and expert opinion support using a combination of an antipsychotic and an antidepressant when treating major depression with psychotic features. We characterized the impact of sertraline co-administration on olanzapine clearance in psychotic depression using population pharmacokinetic methods.

Methods

The Study of Pharmacotherapy for Psychotic Depression (STOP-PD) randomized 259 participants to olanzapine plus placebo or olanzapine plus sertraline. Olanzapine was started at 2.5–5 mg/day and sertraline at 25–50 mg/day. Doses were increased to a maximum of 20 mg/day for olanzapine and 200 mg/day for sertraline. Up to four olanzapine concentration samples were collected during the 12-week trial and 12-week continuation phase. We used NONMEM (Version VII) for population pharmacokinetic analysis, assessing effects of the covariates sex, African American origin, smoking, age, and sertraline co-administration.

Results

Population pharmacokinetic analysis comprised 336 samples from 175 individuals. The structural model published by Bigos et al. was sufficient to describe the olanzapine data adequately: a one-compartment model with first-order absorption and elimination, using an additive residual error structure with the absorption rate constant fixed to 0.5. Sertraline co-administration significantly increased olanzapine apparent clearance (p < 0.005) by 25–35 % depending on the patient characteristics included. Male sex was associated with a significantly increased clearance. Age and race did not have a significant impact on clearance.

Conclusions

Contrary to expectations from the knowledge of cytochrome P450 interactions, sertraline increased olanzapine apparent clearance. Plausible explanations include patients treated with sertraline having poorer adherence to olanzapine, or the impact of sertraline inhibition of transporters resulting in increased intracellular concentrations and thus access to metabolizing enzymes.

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Acknowledgments

Sources of funding: STOP-PD was supported by Grant Nos. MH 62446, MH 62518, MH 62565, and MH 62624 from the US Public Health Service; Grant Nos. MH069430, MH067710, and P30 MH068368 from the National Institute of Mental Health; and Grant Nos. M01-RR024153, RR000056, and CTSC UL1RR024996 from the National Center for Research Resources. Dr. Bies’ work is funded by the Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada.

Financial disclosures/conflict of interest

Eli Lilly provided olanzapine and Pfizer provided sertraline (or matching placebo) for this trial. In addition neither Eli Lilly nor Pfizer participated in the design or conduct of the study or in this analysis. The authors had the following potential conflict of interest: B.H. Mulsant has received grant support or honoraria from the National Institute of Health, the Canadian Institutes for Health Research, AstraZeneca, Bristol-Myers Squibb, Corcept, Eisai, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Janssen, Lundbeck, and Pfizer. A.J. Flint receives grant support from the National Institute of Mental Health, the Canadian Institutes of Health Research, Ontario Brain Institute, Brain Canada, and Lundbeck. He has received honoraria from Janssen-Ortho, Lundbeck Canada, and Pfizer Canada. A.J. Rothschild receives grant or research support from Cyberonics, the National Institute of Mental Health, St Jude Medical, Takeda, AssureRx and Alkermesand is a consultant to Allergan, Eli Lilly and Company, GlaxoSmithKline, Noven Pharmaceuticals, Pfizer Inc, Shire Pharmaceuticals, and Sunovion. E.M. Whyte has received grant support or honoraria from Pfizer, Forest Laboratories, Ortho-McNeil, NIMH, and the NICHD/National Center for Medical Rehabilitation Research. B.G. Pollock receives research support from the National Institute of Health, Canadian Institutes of Health Research, American Psychiatric Association and the Foundation of the Centre for Addiction and Mental Health. He has been a faculty member of the Lundbeck International Neuroscience Foundation (last meeting was April 2010). R.R. Bies is funded through the Indiana Clinical Translational Sciences Institute from a gift of Eli Lilly and Company and the Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada. Dr. Bies is also a scientific advisory board member for the Metrum Institute, Biogen-IDEC and a consultant for INC Research. Dr. Bies has also received travel support from Roche and Sanofi Aventis. S.J.C. Davies, B.S. Meyers, M.M. Kirshner, and D. Sorisio report no conflicts of interest.

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Authors and Affiliations

  1. Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, ON, M6J 1H4, Canada

    Simon J. C. Davies, Benoit H. Mulsant, Bruce G. Pollock & Robert R. Bies

  2. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Simon J. C. Davies, Benoit H. Mulsant, Alastair J. Flint & Bruce G. Pollock

  3. Department of Psychiatry, University Health Network, Toronto, ON, Canada

    Alastair J. Flint

  4. Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, NY, USA

    Barnett S. Meyers

  5. University of Massachusetts Medical School and University of Massachusetts Memorial Health Care, Worcester, MA, USA

    Anthony J. Rothschild

  6. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Ellen M. Whyte & Denise Sorisio

  7. Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Margaret M. Kirshner

  8. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada

    Robert R. Bies

  9. Indiana Clinical and Translational Sciences Institute, Indianapolis, IN, USA

    Robert R. Bies

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  1. Simon J. C. Davies
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  2. Benoit H. Mulsant
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  3. Alastair J. Flint
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  10. Robert R. Bies
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Corresponding author

Correspondence to Simon J. C. Davies.

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For the STOP-PD Study Group.

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Davies, S.J.C., Mulsant, B.H., Flint, A.J. et al. The Impact of Sertraline Co-Administration on the Pharmacokinetics of Olanzapine: A Population Pharmacokinetic Analysis of the STOP-PD. Clin Pharmacokinet 54, 1161–1168 (2015). https://doi.org/10.1007/s40262-015-0275-1

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