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Berm E.J.J.,University of Groningen | Odigie B.,University of Groningen | Bijlsma M.J.,University of Groningen | Wilffert B.,University of Groningen | And 2 more authors.
Bioanalysis | Year: 2016

Background: A bridging study of plasma and DBS concentrations for therapeutic drug monitoring of antidepressants was performed. Results & methodology: Potassium-based hematocrit analysis was included. In addition, we defined acceptance criteria based on the differences between individual data points of plasma and DBS concentrations. These criteria were applied to test acceptability of error found in predicted nortriptyline plasma concentrations. Potassium-based hematocrit predicted a negative bias for DBS concentrations of amitriptyline, but not for the other compounds. To predict plasma concentrations of antidepressants based on DBS concentrations, a factor of 0.8, 0.65, 0.84 and 0.78 was found for nortriptyline, desmethylclomipramine, venlafaxine and desmethylvenlafaxine, respectively. Discussion & conclusion: Application of the factor and newly formulated acceptance criteria demonstrated prediction of nortriptyline plasma concentrations based on DBS concentrations. © 2016 Future Science Ltd.


Berm E.J.J.,University of Groningen | Hak E.,University of Groningen | Postma M.,University of Groningen | Boshuisen M.,Lentis | And 14 more authors.
Trials | Year: 2015

Background: Nortriptyline and venlafaxine are commonly used antidepressants for treatment of depression in older patients. Both drugs are metabolized by the polymorphic cytochrome P450-2D6 (CYP2D6) enzyme and guidelines for dose adaptations based on the CYP2D6 genotype have been developed. The CYP2D6 Screening Among Elderly (CYSCE) trial is designed to address the potential health and economic value of genotyping for CYP2D6 in optimizing dose-finding of nortriptyline and venlafaxine. Methods/Design: In a pragmatic randomized controlled trial, patients diagnosed with a major depressive disorder according to the DSM-IV and aged 60 years or older will be recruited from psychiatric centers across the Netherlands. After CYP2D6 genotyping determined in peripheral blood obtained by finger-prick, patients will be grouped into poor, intermediate, extensive, or ultrarapid metabolizers. Patients with deviant genotype (that is poor, intermediate or ultrarapid genotype) will be randomly allocated to an intervention group in which the genotype and dosing advice is communicated to the treating physician, or to a control group in which patients receive care as usual. Additionally, an external reference group of patients with the extensive metabolizer genotype is included. Primary outcome in all groups is time needed to obtain an adequate blood level of the antidepressant drug. Secondary outcomes include adverse drug reactions measured by a shortened Antidepressant Side-Effects Checklist (ASEC), and cost-effectiveness of the screening. Discussion: Results of this trial will guide policy-making with regard to pharmacogenetic screening prior to treatment with nortriptyline or venlafaxine among older patients with depression. © 2015 Berm et al.


Berm E.J.J.,University of Groningen | Brummel-Mulder E.,Laboratory for Drug Analysis and Toxicology | Paardekooper J.,Laboratory for Drug Analysis and Toxicology | Hak E.,University of Groningen | And 2 more authors.
Analytical and Bioanalytical Chemistry | Year: 2014

Dried blood spot (DBS) sampling and quantitative analyses of many current therapeutic drug monitoring (TDM)-guided drugs are advantageous because of the minimal invasive sampling strategy. Here, a fast and robust LC-MS/MS method was developed and analytically validated for simultaneous determination of venlafaxine (VEN) and O-desmethylvenlafaxine (ODV) in DBS. Six-millimeter circles were punched out from DBS collected on Whatman DMPK-C paper, and the DBS was extracted with acetonitrile/methanol at 1:3. The total run time was 4.8 min. The assay was linear in the range of 20-1,000 μg/L for both VEN and ODV. Assay accuracy and precision was well within limits of acceptance (LLOQ∈=∈20 μg/L). Normal hematocrit concentrations (0.30-0.50) did not influence the results neither did a normal spot volume (40-80 μL). Punch position at the perimeter instead of the center of the blood spot gave a bias ranging from 2.4 to 10.4 %. Correlation between plasma and spiked DBS samples was high. The concentrations found in spiked DBS samples were higher than those in plasma, indicating that a conversion factor for translation of DBS to plasma values is needed. This analytically validated method is suitable for determination of VEN and ODV in DBS and applicable for TDM. The method will be used for TDM of VEN in the Dutch CYSCE multicenter trial (NCT01778907). © 2014 Springer-Verlag Berlin Heidelberg.


Berm E.J.J.,University of Groningen | Paardekooper J.,Laboratory for Drug Analysis and Toxicology | Brummel-Mulder E.,Laboratory for Drug Analysis and Toxicology | Hak E.,University of Groningen | And 2 more authors.
Talanta | Year: 2015

Therapeutic drug monitoring (TDM) of tricyclic antidepressants (TCAs) is considered useful in patients with major depressive disorder, since these drugs display large individual differences in clearance, and the therapeutic windows of these drugs are relatively small. We developed an assay for determination of amitriptyline (ATP), nortriptyline (NTP), imipramine (IMP), desipramine (DSP) clomipramine (CMP) and desmethyl-clomipramine (DCMP) in dried blood spots (DBS). A fast and robust LC-MS/MS method was developed and analytically validated for simultaneous determination of ATP, NTP, IMP, DSP, CMP, and DCMP in DBS. Six mm circles were punched out from DBS collected on Whatman DMPK-C paper and mixed with acetonitrile: methanol 1:3 containing the internal standard. The extract was analyzed by LC-MS/MS. Total LC-MS/MS runtime was 4.8 min. The assay was linear in the range 20-500 μg/L for all compounds. Overall-assay accuracy and precision were<20% for the lower limit of quantification (LLOQ), except for CMP (CV=22.3%), and<15% at other concentrations. The initial LLOQ was 20 μg/L however for CMP and DMCP it was increased to 40 μg/L. The blood volume per spot did not influence the results, but a low hematocrit (≤ 30%) was associated with a>15% negative bias for all compounds. Punching at the perimeter of the blood spot instead of the center was associated with a positive bias. A good correlation was found between patients plasma and DBS samples of ATP, NTP and DMCP, but not for CMP. In addition, proportional differences were found. This LC-MS/MS method was analytically validated for determination of TCAs in DBS. Future validation will focus on the clinical application of the method. © 2014 Elsevier B.V. All rights reserved.

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