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Impact of age and CYP2D6 genotype on exposure of zuclopenthixol in patients using long-acting injectable versus oral formulation—an observational study including 2044 patients

  • Pharmacokinetics and Disposition
  • Published:
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Abstract

Purpose

Zuclopenthixol is an antipsychotic available as oral and long-acting injectable (LAI) formulations. The aim of this study was to investigate the effect of age on zuclopenthixol exposure during oral and LAI administrations without and with adjustment for CYP2D6 genotype.

Methods

Data on serum concentrations of zuclopenthixol and CYP2D6 genotype (available for 28.2% of the population) from patients using oral or LAI zuclopenthixol were included retrospectively from a therapeutic drug monitoring service during the period 2005–2019. As a measure of exposure, dose-adjusted serum concentration (C/D ratio) was used. Based on age, patients were grouped to older (≥ 65 years) or younger (18–64 years). Linear mixed model analyses without and with adjustment for CYP2D6 genotype were used.

Results

Serum concentrations of zuclopenthixol from 1145 (14.1% older) and 899 patients (24.6% older) in the LAI and oral groups were included, respectively. Compared with younger patients, older patients had a higher C/D ratio of zuclopenthixol for LAI (+ 25–33%, p < 0.001) and oral formulation (+ 25–29%, p ≤ 0.003) without and with adjustment for CYP2D6 genotype. The doses were lower in older versus younger patients (oral: − 30%; LAI: − 20%; p < 0.001). Compared with the younger LAI users without reduced CYP2D6 function, a higher C/D ratio was observed in the older LAI users with reduced CYP2D6 function (+ 104%, p < 0.001).

Conclusion

The present study showed that zuclopenthixol exposure increases in older patients and that the older LAI users with reduced CYP2D6 function are exposed to high serum concentrations. Also, the present study showed that similar dose reductions are required for oral and LAI users.

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Data availability

The data that supports the findings of this study are available upon reasonable request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions.

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Funding

This work was funded by the South-Eastern Norway Regional Health Authority (grant number 2017085).

Author information

Authors and Affiliations

  1. Center for Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, 0319, Oslo, Norway

    Marit Tveito, Robert Løvsletten Smith, Espen Molden & Gudrun Høiseth

  2. Norwegian National Advisory Unit on Aging and Health, Vestfold Hospital Trust, Tønsberg, Norway

    Marit Tveito

  3. Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway

    Espen Molden

  4. Department of Forensic Sciences, Oslo University Hospital, Oslo, Norway

    Gudrun Høiseth

  5. Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Gudrun Høiseth

Authors
  1. Marit Tveito
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  2. Robert Løvsletten Smith
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  3. Espen Molden
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  4. Gudrun Høiseth
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Contributions

All authors were involved in the ideation, conceptualisation, and design of the study. RLS and MT collected and prepared the data material. RLS analysed the data. RLS, MT, and GH interpreted the data. MT, RLS, and GH drafted the manuscript. All other authors critically reviewed the manuscript and approved the submitted version.

Corresponding author

Correspondence to Marit Tveito.

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Conflict of interest

Prof. Molden has received speaker’s honoraria from Lundbeck and Lilly. The other authors have no conflicts of interest to declare.

Ethics approval

The study was approved by the Regional Committee for Medical and Health Research Ethics (2017/9121) and Health Research Ethics and the Hospital Investigational Review Board.

Consent to participate

The use of historical patient data for the purpose of this study was approved by the Regional Committee for Medical and Health Research Ethics and the Hospital Investigational Review Board without consent from the patients, as the study was based on retrospective data only.

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All authors have approved the submission.

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Marit Tveito and Robert Løvsletten Smith shared first authorship.

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Tveito, M., Smith, R.L., Molden, E. et al. Impact of age and CYP2D6 genotype on exposure of zuclopenthixol in patients using long-acting injectable versus oral formulation—an observational study including 2044 patients. Eur J Clin Pharmacol 77, 215–221 (2021). https://doi.org/10.1007/s00228-020-03002-y

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  • DOI: https://doi.org/10.1007/s00228-020-03002-y

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