Impact of age and CYP2D6 genetics on exposure of aripiprazole and dehydroaripiprazole in patients using long-acting injectable versus oral formulation: relevance of poor and intermediate metabolizer status

Tveito, Marit; Molden, Espen; Høiseth, Gudrun; Correll, Christoph U.; Smith, Robert L.

doi:10.1007/s00228-019-02768-0

Cited by 15 publications

(13 citation statements)

References 47 publications

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“…The present results are however in accordance with previous results for olanzapine; doses are reduced in older patients, leading to lower absolute concentrations [13]. Dose reductions for older patients are also previously documented for aripiprazole [14]. The present study showed more moderately reduced doses in the LAI group, making absolute concentrations more similar in the oldest and youngest patients.…”

Section: Discussionsupporting

confidence: 93%

“…Another earlier study actually concluded that no effect of age was seen on C/D ratios for olanzapine or clozapine, but only patients above 50 years were studied specifically [21]. For drugs like risperidone [11] and aripiprazole [14], the situation is shown to be complicated, with no age effect on the mother substance, but increased metabolite concentrations with age. The present study adds knowledge to previous results, placing zuclopenthixol among drugs where clinically relevant pharmacokinetic changes are seen in older patients, but of modest degree.…”

Section: Discussionmentioning

confidence: 99%

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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

Tveito

Smith

Molden

et al. 2020

Eur J Clin Pharmacol

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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.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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

Tveito

Smith

Molden

et al. 2020

Eur J Clin Pharmacol

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“…7 CYP2D6 genotypes influence the plasma concentrations of aripiprazole. [8][9][10] The consensus on the therapeutic range for aripiprazole, therefore, consists of the sum of the parent drug and the metabolite, which is the active moiety. 11 The plasma concentrations of dehydroaripiprazole are lower than those of aripiprazole after a single oral dose and at steady state.…”

Section: Introductionmentioning

confidence: 99%

Relationship of Prolactin Concentrations to Steady-State Plasma Concentrations of Aripiprazole in Patients With Schizophrenia

Tasaki

Yasui‐Furukori

Kubo

et al. 2021

Therapeutic Drug Monitoring

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Background: Aripiprazole is regarded as the first-line antipsychotic medication. Long-term aripiprazole therapy can cause hypoprolactinemia, which may result from its activity as a dopamine agonist. However, there is little information on hypoprolactinemia and steady-state aripiprazole concentrations. Methods:The subjects included 66 male and 177 female patients diagnosed with schizophrenia who were treated with aripiprazole. The plasma concentrations of aripiprazole and dehydroaripiprazole and the plasma concentration of prolactin were measured using highperformance liquid chromatography and enzyme immunoassay, respectively. A prolactin concentration of ,5 ng/mL was defined as hypoprolactinemia.Results: Fifty-two of the 66 male patients (79%) and 58 of the 177 female patients (33%) had hypoprolactinemia. There were significant inverse correlations between plasma prolactin levels and plasma concentrations of aripiprazole (r s = 20.447, P , 0.001) and the active moiety (aripiprazole plus dehydroaripiprazole) (r s = 20.429, P , 0.001) in men. In women, significant inverse correlations were also found between plasma prolactin levels and plasma concentrations of aripiprazole (r s = 20.273, P , 0.01) and the active moiety (r s = 20.275, P , 0.01).Conclusions: These findings suggest that lower prolactin levels are, to some extent, associated with higher plasma drug concentrations in male and female patients with schizophrenia treated with aripiprazole.

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“…Current FDA recommendation only takes into account dose adjustment in CYP2D6 PMs, but available studies show that dose reduction should also be carried out in CYP2D6 IMs. In this sense, Tveito et al [ 102 ] established that IM phenotype increases aripiprazole plasma concentration by 50% and active moiety concentration by 40%, both compared to NM. Further pharmacogenetic studies must be carried out in order to confirm this effect on plasma exposure, which could entail updating the product information regarding this group of patients.…”

Section: Long-acting Aripiprazolementioning

confidence: 99%

“…Further pharmacogenetic studies must be carried out in order to confirm this effect on plasma exposure, which could entail updating the product information regarding this group of patients. Among all the studies, only a few of them were performed with AOM, in which substantial influence of CYP2D6 phenotype on serum concentrations was observed too, as in oral formulations [ 102 ].…”

Section: Long-acting Aripiprazolementioning

confidence: 99%

Review of Pharmacokinetics and Pharmacogenetics in Atypical Long-Acting Injectable Antipsychotics

et al. 2021

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Over the last two decades, pharmacogenetics and pharmacokinetics have been increasingly used in clinical practice in Psychiatry due to the high variability regarding response and side effects of antipsychotic drugs. Specifically, long-acting injectable (LAI) antipsychotics have different pharmacokinetic profile than oral formulations due to their sustained release characteristics. In addition, most of these drugs are metabolized by CYP2D6, whose interindividual genetic variability results in different metabolizer status and, consequently, into different plasma concentrations of the drugs. In this context, there is consistent evidence which supports the use of therapeutic drug monitoring (TDM) along with pharmacogenetic tests to improve safety and efficacy of antipsychotic pharmacotherapy. This comprehensive review aims to compile all the available pharmacokinetic and pharmacogenetic data regarding the three major LAI atypical antipsychotics: risperidone, paliperidone and aripiprazole. On the one hand, CYP2D6 metabolizer status influences the pharmacokinetics of LAI aripiprazole, but this relation remains a matter of debate for LAI risperidone and LAI paliperidone. On the other hand, developed population pharmacokinetic (popPK) models showed the influence of body weight or administration site on the pharmacokinetics of these LAI antipsychotics. The combination of pharmacogenetics and pharmacokinetics (including popPK models) leads to a personalized antipsychotic therapy. In this sense, the optimization of these treatments improves the benefit–risk balance and, consequently, patients’ quality of life.

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Impact of age and CYP2D6 genetics on exposure of aripiprazole and dehydroaripiprazole in patients using long-acting injectable versus oral formulation: relevance of poor and intermediate metabolizer status

Cited by 15 publications

References 47 publications

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

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

Relationship of Prolactin Concentrations to Steady-State Plasma Concentrations of Aripiprazole in Patients With Schizophrenia

Review of Pharmacokinetics and Pharmacogenetics in Atypical Long-Acting Injectable Antipsychotics

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