Genotype and co-medication dependent CYP2D6 metabolic activity: effects on serum concentrations of aripiprazole, haloperidol, risperidone, paliperidone and zuclopenthixol.

Patteet , Lisbeth;Haufroid, Vincent;Maudens , Kristof;Sabbe , Bernard;Neels , Hugo;et.al.
(2016) European Journal of Clinical Pharmacology — Vol. 72, n° 2, p. 175-184 (2016)

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Authors
  • Patteet , Lisbeth
    Author
  • Haufroid, Vincentorcid-logoUCLouvain
    Author
  • Maudens , Kristof
    Author
  • Sabbe , Bernard
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  • Neels , Hugo
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Abstract
PURPOSE: Therapeutic drug monitoring (TDM) of antipsychotics can aid in therapy optimization, explaining adverse effects or non-response. One reason for therapeutic failure or adverse effects is caused by genetic variations in the cytochrome P450 drug-metabolizing genes. The aim of this study was to evaluate the impact of CYP2D6 polymorphisms on steady-state serum concentrations of antipsychotics metabolized by CYP2D6, taking into account the co-medication with CYP2D6 inhibitors. METHODS: Serum and EDTA samples were collected from 82 psychiatric patients. After a liquid-liquid extraction, serum samples were analyzed using an ultra-high performance liquid chromatography-tandem mass spectrometric (UHPLC-MS/MS) method for quantification of the antipsychotics. CYP2D6 genotyping was performed using the Luminex xTAG® CYP2D6 Kit v3 (Luminex Corporation). Patients were divided into five phenotype subgroups by calculation of the activity score (AS): poor metabolizers (PM; AS 0), intermediate metabolizers (IM; AS 0.5-1), extensive metabolizers with slow activity (EM-s; AS 1-1.5), extensive metabolizers with fast activity (EM-f; AS 2), and ultra-rapid metabolizers (UM; AS >2). The influence of the phenotypes on the concentration-to-dose and metabolite-to-parent ratios was evaluated. RESULTS: Overall, 6.1 % UM (n = 5), 25.6 % EM-f (n = 21), 46.3 % EM-s (n = 38), 1.2 % EM-s/EM-f (n = 1), 6.1 % IM (n = 5), and 14.6 % PM (n = 12) were found, taking co-administration of strong and moderate CYP2D6 inhibitors into account (phenoconversion). It was demonstrated that CYP2D6 polymorphisms affect the serum concentrations of aripiprazole (n = 18), haloperidol (n = 11), risperidone (n = 20), and zuclopenthixol (n = 6), while no influence was seen on the paliperidone serum concentrations (n = 31). CONCLUSIONS: Even with a small number of patients per antipsychotic, the importance of CYP2D6 genotyping was still clearly stated. This study illustrates the high potential of combining TDM and CYP2D6 genotyping in clinical practice.
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Patteet, L., Haufroid, V., Maudens, K., Sabbe, B., Morrens, M., & Neels, H. (2016). Genotype and co-medication dependent CYP2D6 metabolic activity: effects on serum concentrations of aripiprazole, haloperidol, risperidone, paliperidone and zuclopenthixol. European Journal of Clinical Pharmacology, 72(2), 175-184. https://doi.org/10.1007/s00228-015-1965-1 (Original work published 2016)