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Lisbeth P.,University of Antwerp | Vincent H.,Catholic University of Louvain | Kristof M.,University of Antwerp | Bernard S.,University of Antwerp | And 4 more authors.
European Journal of Clinical Pharmacology | Year: 2016

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. © 2015 Springer-Verlag Berlin Heidelberg.


Maudens K.E.,University of Antwerp | Patteet L.,University of Antwerp | van Nuijs A.L.N.,University of Antwerp | Van Broekhoven C.,University of Antwerp | And 3 more authors.
Forensic Science International | Year: 2014

The volume of distribution of ethanol was already established in 1930s by Widmark. However, since then the average body composition has changed considerably. The effect of the body mass index (BMI) on the volume of distribution of ethanol was evaluated in this study. Fifty healthy volunteers (23 men and 27 women), with BMI-values between 16.0 and 36.0kg/m2, were asked to drink a dose of 0.4g ethanol per kilogram body weight after an overnight fast. The ethanol content was measured by a fully validated headspace-GC-FID method. The volume of distribution of ethanol varied between 0.40 and 0.68L/kg for women, and between 0.43 and 0.73L/kg for men. For both sexes, the volume of distribution decreased with increasing BMI. Regression analysis resulted in the following equations: volume of distribution=0.8202-0.0090×BMI for men (r=0.66), and 0.7772-0.0099×BMI for women (r=0.78). Population probability prediction interval limits were also calculated. In view of the current study, fixed values for the volume of distribution of 0.7L/kg and 0.6L/kg for men and women, respectively, often applied in legal blood alcohol calculations, are mainly suited to judge underweight or normal weight people, but not obese persons. © 2014 Elsevier Ireland Ltd.


Patteet L.,University of Antwerp | Morrens M.,University of Antwerp | Maudens K.E.,University of Antwerp | Niemegeers P.,University of Antwerp | And 4 more authors.
Therapeutic Drug Monitoring | Year: 2012

The aim of this review is to provide information for interpreting outcome results from monitoring of antipsychotics in biological samples. A brief overview of the working mechanisms, pharmacological effects, drug interactions, and analytical methods of classical and atypical antipsychotics is given. Nineteen antipsychotics were selected based on their importance in the worldwide market as follows: amisulpride, aripiprazole, asenapine, bromperidol, clozapine, flupenthixol, haloperidol, iloperidone, lurasidone, olanzapine, paliperidone, perphenazine, pimozide, pipamperone, quetiapine, risperidone, sertindole, sulpiride, and zuclopenthixol. A straightforward relationship between administered dose, plasma or serum concentration, clinical outcome, or adverse effects is often lacking. Nowadays, focus lies on therapeutic drug monitoring and individualized therapy to find adequate treatment, to explain treatment failure or nonresponse, and to check patient compliance. However, extensive research in this field is still mandatory. Copyright © 2012 by Lippincott Williams & Wilkins.


Patteet L.,University of Antwerp | Patteet L.,Laboratory for TDM and Toxicology | Maudens K.E.,University of Antwerp | Sabbe B.,University of Antwerp | And 5 more authors.
Clinica Chimica Acta | Year: 2014

Background: Therapeutic drug monitoring of antipsychotics is important for optimizing therapy, explaining adverse effects, non-response or poor compliance. We developed a UHPLC-MS/MS method for quantification of 16 commonly used and recently marketed antipsychotics and 8 metabolites in serum. Methods: After liquid-liquid extraction using methyl tert-butyl ether, analysis was performed on an Agilent Technologies 1290 Infinity LC system coupled with an Agilent Technologies 6460 Triple Quadrupole MS. Separation with a C18 column and gradient elution at 0.5. mL/min resulted in a 6-min run-time. Detection was performed in dynamic MRM, monitoring 3 ion transitions per compound. Isotope labeled internal standards were used for every compound, except for bromperidol and levosulpiride. Results: Mean recovery was 86.8%. Matrix effects were -. 18.4 to +. 9.1%. Accuracy ranged between 91.3 and 107.0% at low, medium and high concentrations and between 76.2 and 113.9% at LLOQ. Within-run precision was <. 15% (CV), except for asenapine and hydroxy-iloperidone. Between-run precision was aberrant only for 7-hydroxy-N-desalkylquetiapine, asenapine and reduced haloperidol. No interferences were found. No problems of instability were observed, even for olanzapine. The method was successfully applied on patient samples. Conclusions: The liquid-liquid extraction and UHPLC-MS/MS technique allows robust target screening and quantification of 23 antipsychotics and metabolites. © 2013 Elsevier B.V.


Patteet L.,University of Antwerp | Patteet L.,Laboratory for TDM and Toxicology | Maudens K.E.,University of Antwerp | Stove C.P.,Ghent University | And 6 more authors.
Bioanalysis | Year: 2015

DBS sampling has been proposed as an alternative for venous blood collection in therapeutic drug monitoring (TDM) of antipsychotics. For implementation in routine practice, a comparison between capillary and venous blood concentrations is mandatory. Results: A DBS method for quantification of antipsychotics was clinically validated. First, whole blood therapeutic ranges were calculated using the blood:serum ratio. Calculation of DBS:blood ratios and Passing-Bablok regression analysis demonstrated that concentrations obtained by DBS analysis were highly comparable to those obtained by conventional whole blood analysis. Clinical interpretation of serum, whole blood and DBS concentrations were highly identical (sensitivity 91.6-97.6%). Conclusion: This is the first clinical study demonstrating the value of DBS sampling in TDM of antipsychotics. © 2015 Future Science Ltd.

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