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

Abstract

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. MethodsData 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. ResultsSerum concentrations of zuclopenthixol from 1,145 (14.1% older) and 899 patients (24.6% older) in the LAI and oral group were included, respectively. Compared to younger patients, older patients had 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 to 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). ConclusionThe 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.

Impact of age, sex and cytochrome P450 genotype on quetiapine and N‐desalkylquetiapine serum concentrations: A study based on real‐world data from 8118 patients

“…As the indication for use is unknown, the observed lower doses prescribed to the elderly could also be due to the use of quetiapine for other indications than in the younger population, for example, lower doses are used for the treatment of depression compared to the doses used to treat schizophrenia. The lower doses in the elderly are reflected in lower absolute concentrations of QUE and NDQ at higher ages (Figure 2), as observed for other antipsychotics 29,30 …”

“…The lower doses in the elderly are reflected in lower absolute concentrations of QUE and NDQ at higher ages (Figure 2), as observed for other antipsychotics. 29,30 The variability in C:D ratios of QUE and NDQ, both total and intraindividual (shown in Figure 1), are large. Therefore, a large patient material, which was available for this study, is required for proper estimation of the impact of age, sex and CYP genotypes.…”

Automated Interlaboratory Comparison of Therapeutic Drug Monitoring Data and Its Use for Evaluation of Published Therapeutic Reference Ranges

“…However, the difference may also be due to the naturalistic setting of the data sets in this study, compared with a controlled population. Both perphenazine and zuclopenthixol have been found to be strongly influenced by the metabolic status of the CYP2D6 enzyme [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. For these drugs, patients prescribed a standard dosage and who are either poor metabolisers or subject to drug interactions are expected to harbour a higher serum concentration.…”