Impact of age and CYP2D6 genotype on exposure of zuclopenthixol in patients using long-acting injectable versus oral for
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PHARMACOKINETICS AND DISPOSITION
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 Marit Tveito 1,2
&
Robert Løvsletten Smith 1
&
Espen Molden 1,3
&
Gudrun Høiseth 1,4,5
Received: 9 July 2020 / Accepted: 16 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords Zuclopenthixol . Long-acting injectable . Age . CYP2D6 genotype Marit Tveito and Robert Løvsletten Smith shared first authorship. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00228-020-03002-y) contains supplementary material, which is available to authorized users. * Marit Tveito [email protected] 1
Center for Psychopharmacology, Diakonhjemmet Hospital, PO Box 85, Vinderen, 0319 Oslo, Norway
2
Norwegian National Advisory Unit on Aging and Health, Vestfold Hospital Trust, Tønsberg, Norway
3
Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway
4
Department of Forensic Sciences, Oslo University Hospital, Oslo, Norway
5
Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Introduction Schizophrenia is a severe mental disorder affecting about 1% of the world’s population [1]. Although person
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