Laboratory for TDM and Toxicology

Antwerpen, Belgium

Laboratory for TDM and Toxicology

Antwerpen, Belgium
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Niemegeers P.,University of Antwerp | Dumont G.J.,University of Antwerp | Patteet L.,University of Antwerp | Neels H.,University of Antwerp | And 3 more authors.
Expert Opinion on Drug Metabolism and Toxicology | Year: 2013

Introduction: Seasonal affective disorder (SAD) is a psychiatric illness with recurring depressive episodes during particular seasons, mostly winter. Bupropion is effective in the preventive treatment of SAD and is probably also effective in the acute treatment of SAD. Areas covered: This review covers the pharmacokinetics and pharmacodynamics of bupropion. The authors also evaluate bupropion's clinical efficacy as well as its safety and tolerability. Expert opinion: Bupropion is available in an immediate release formulation, as well as a sustained release formulation and an extended release (XR) formulation. The XR formulation is recommended for SAD due to its ease of use and is the only formulation currently used as a therapy. Due to the predictable nature of SAD, the use of bupropion XR is considered a relevant treatment option. Bupropion's efficacy is shown in three trials that started in autumn at a time when SAD symptoms were not yet present although treatment effects were relatively small compared with a placebo. Bupropion was also shown to have efficacy in an open-label study. That being said, in order to reach definitive conclusions about its efficacy with acute treatment of SAD, more placebo-controlled trials are needed. © 2013 Informa UK, Ltd.


Niemegeers P.,University of Antwerp | Maudens K.E.,University of Antwerp | Morrens M.,University of Antwerp | Morrens M.,Psychiatric Hospital Broeders Alexianen | And 6 more authors.
Expert Opinion on Drug Metabolism and Toxicology | Year: 2012

Introduction: Bipolar disorder is a psychiatric illness with recurring episodes of mania and depression. Armodafinil, the R-enantiomer of modafinil, approved for treating excessive sleepiness associated with narcolepsy, obstructive sleep apnea and shift work disorder, is possibly effective as an adjunctive treatment for bipolar depression. Areas covered: This review covers the pharmacokinetics of armodafinil, with an emphasis on its use in bipolar depression. Its clinical efficacy in the treatment of bipolar depression is evaluated, along with current data regarding its safety and tolerability. Expert opinion: One placebo-controlled trial is available, in which armodafinil was efficacious as an adjunctive treatment in bipolar depression. Armodafinil shows a linear pharmacokinetic profile over a broad dose range of 50 400 mg (maximal plasma concentration and area under concentrationtime curve). Compared with modafinil, an equivalent dose of armodafinil attains higher blood concentrations 4 6 h post-dose. The possibility of drug interactions is generally low, although interactions have been shown with some drugs used in bipolar disorder, through mild CYP3A4-induction and CYP2C19-inhibition. Armodafinil is well tolerated and presents a possible new treatment option for bipolar depression. However, further investigation is still needed in order to confirm its efficacy and to clarify its role in the treatment of bipolar depression. © 2012 Informa UK, Ltd.


Kurdi A.,University of Antwerp | De Doncker M.,Laboratory for TDM and Toxicology | Leloup A.,University of Antwerp | Neels H.,Laboratory for TDM and Toxicology | And 6 more authors.
British Journal of Pharmacology | Year: 2016

Background and Purpose: Everolimus is an allosteric inhibitor of the mechanistic target of rapamycin complex 1 (mTORC1) widely known for its potent autophagy stimulating properties. Because everolimus shows poor solubility and stability in aqueous solutions, long-term in vivo administration in preclinical models is challenging. The aim of the present study was to evaluate the effects of short-term and long-term everolimus administration on mTORC1 inhibition and autophagy induction in mice. Experimental Approach: We developed a vehicle in which everolimus was solubilized and stable at 37°C for at least 1 month. Using osmotic minipumps, GFP microtubule-associated protein light chain 3 transgenic mice were treated continuously either with vehicle or everolimus (1.5 mg·kg−1 per day) for 3 or 28 days. Alternatively, a regimen consisting of intermittent everolimus administration (every other day) for 56 days by oral gavage was used. Autophagy markers and mTORC1 activation status were investigated in the liver. Key Results: As expected, everolimus inhibited mTORC1 and stimulated autophagy in the liver after 3 days of treatment. However, continuous administration for 28 days resulted in hyperactivation of the Akt1-mTORC1 pathway accompanied by a remarkable decrease in autophagy markers. Everolimus given intermittently for 56 days partially rescued mTORC1 sensitivity to the drug but without inducing autophagy. The failure to induce autophagy following long-term everolimus administration was due to uncoupling of the mTORC1 substrate unc-51 like autophagy activating kinase 1. Conclusions and Implications: Our data encourage the use of intermittent everolimus regimens to prevent tolerance and to extend its activity. © 2016 The British Pharmacological Society


Patteet L.,University of Antwerp | Patteet L.,Laboratory for TDM and Toxicology | Maudens K.E.,University of Antwerp | Sabbe B.,University of Antwerp | And 6 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 | Morrens M.,University of Antwerp | Morrens M.,Psychiatric Hospital Broeders Alexianen | Maudens K.E.,University of Antwerp | And 5 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 | Stove C.P.,Ghent University | And 5 more authors.
Drug Testing and Analysis | Year: 2015

Therapeutic drug monitoring of antipsychotics is important in optimizing individual therapy. In psychiatric populations, classical venous blood sampling is experienced as frightening. Interest in alternative techniques, like dried blood spots (DBS), has consequently increased. A fast and easy to perform DBS method for quantification of 16 antipsychotics (amisulpride, aripiprazole, asenapine, bromperidol, clozapine, haloperidol, iloperidone, levosulpiride, lurasidone, olanzapine, paliperidone, pipamperone, quetiapine, risperidone, sertindole and zuclopenthixol) and 8 metabolites was developed. DBS were prepared using 25μL of whole blood and extraction of complete spots was performed using methanol: methyl-t-butyl-ether (4:1). After evaporation, the extract was reconstituted in the mobile phase and 10μL were injected on an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Separation using a C18 column and gradient elution with a flow rate of 0.5mL/min resulted in a 6-min run-time. Ionization was performed in positive mode and a dynamic MRM method was applied. Median recovery was 66.4 % (range 28.7-84.5%). Accuracy was within the acceptance criteria, except for pipamperone (LLOQ and low concentration) and lurasidone (low concentration). Imprecision was only aberrant for lurasidone at low and medium concentration. All compounds were stable during 1month at room temperature, 4°C and -18°C. Lurasidone was unstable when the extract was stored for 12h on the autosampler. Absolute matrix effects (ME) (median 66.1%) were compensated by the use of deuterated IS (median 98.8%). The DBS method was successfully applied on 25-μL capillary DBS from patients and proved to be a reliable alternative for quantification of all antipsychotics except for olanzapine and N-desmethylolanzapine. © 2014 John Wiley & Sons, Ltd.


Patteet L.,University of Antwerp | Patteet L.,Laboratory for TDM and Toxicology | Cappelle D.,University of Antwerp | Maudens K.E.,University of Antwerp | And 4 more authors.
Clinica Chimica Acta | Year: 2015

Measuring antipsychotic concentrations in human matrices is important for both therapeutic drug monitoring and forensic toxicology. This review provides a critical overview of the analytical methods for detection and quantification of antipsychotics published in the last four years. Focus lies on advances in sample preparation, analytical techniques and alternative matrices. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is used most often for quantification of antipsychotics. This sensitive technique makes it possible to determine low concentrations not only in serum, plasma or whole blood, but also in alternative matrices like oral fluid, dried blood spots, hair, nails and other body tissues. Current literature on analytical techniques for alternative matrices is still limited and often requires a more thorough validation including a comparison between conventional and alternative results to determine their actual value. Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) makes it possible to quantify a high amount of compounds within a shorter run time. This technique is widely used for multi-analyte methods. Only recently, high-resolution mass spectrometry has gained importance when a combination of screening of (un)known metabolites, and quantification is required. © 2014 Elsevier B.V.


Cappelle D.,University of Antwerp | Yegles M.,Laboratoire National Of Sante | Neels H.,University of Antwerp | Neels H.,Laboratory for TDM and Toxicology | And 5 more authors.
Forensic Toxicology | Year: 2015

Nails can stably accumulate substances for long periods of time, thus providing retrospective information regarding drugs of abuse and pharmaceutical use. Nails have several advantages over the conventional matrices, such as blood and urine, including a longer detection window (months to years), non-invasive sample collection, and easy storage and transport. These aspects make nails a very interesting matrix for forensic and clinical toxicology. Because of the low concentrations of drugs of abuse and pharmaceuticals present in nails and the complexity of the keratinized matrix, analytical methods need to be more sensitive, and sample preparation is crucial. This review summarizes the literature regarding the detection and quantification of drugs of abuse and pharmaceuticals in nails, as well as the employed pre-analytical and analytical techniques. Additionally, the applications of nail analysis are reviewed. Finally, an overview of the challenges of nail analysis is provided, and guidelines for future research are proposed. © 2014, Japanese Association of Forensic Toxicology and Springer Japan.


PubMed | Laboratory for TDM and Toxicology and University of Antwerp
Type: Evaluation Studies | Journal: Clinical biochemistry | Year: 2014

Clozapine is an atypical antipsychotic with a narrow therapeutic range and serious toxic side effects. According to AGNP-TDM consensus guidelines, therapeutic drug monitoring (TDM) of clozapine and its metabolite norclozapine is strongly recommended. 330 serum samples, sent to the toxicological laboratory of Ziekenhuis Netwerk Antwerpen for monitoring of clozapine, were tested with a new ultra-high performance liquid chromatography-tandem mass spectrometric method (UHPLC-MS/MS). The aim of this research was to evaluate this method for TDM of clozapine and norclozapine, but also to determine other antipsychotics present in these serum samples.Serum samples were taken just prior to the morning dose of the antipsychotic (trough concentration). All samples were, after a simple liquid-liquid extraction with methyl t-butylether, analyzed using a fully validated UHPLC-MS/MS method which is able to quantitate 16 different antipsychotics and 8 of their major metabolites. Serum concentrations were compared with the therapeutic ranges as defined by the AGNP-TDM guidelines.For clozapine, only 22.3% of the serum concentrations were within the therapeutic range of 350-600 ng/mL, while 67.9% of the concentrations were below 350 ng/mL. For norclozapine, 68.2% of the serum samples were within the therapeutic range of 100-600 ng/mL. The mean clozapine:norclozapine ratio was 1.7 (SD 0.8). 218 of the 330 serum samples contained other antipsychotics than clozapine. Only 52.5% of these concentrations were within the proposed range.This retrospective study highlights the importance of TDM for clozapine and other APs, since many patients show suboptimal serum concentrations.


PubMed | Laboratory for TDM and Toxicology and University of Antwerp
Type: | Journal: British journal of pharmacology | Year: 2016

Everolimus is an allosteric inhibitor of the mechanistic target of rapamycin complex 1 (mTORC1) widely known for its potent autophagy stimulating properties. Because everolimus shows poor solubility and stability in aqueous solutions, long-term in vivo administration in preclinical models is challenging. The aim of the present study was to evaluate the effects of short-term and long-term everolimus administration on mTORC1 inhibition and autophagy induction in mice.We developed a vehicle in which everolimus was solubilized and stable at 37C for at least 1month. Using osmotic minipumps, GFP microtubule-associated protein light chain 3 transgenic mice were treated continuously either with vehicle or everolimus (1.5mgkgAs expected, everolimus inhibited mTORC1 and stimulated autophagy in the liver after 3days of treatment. However, continuous administration for 28days resulted in hyperactivation of the Akt1-mTORC1 pathway accompanied by a remarkable decrease in autophagy markers. Everolimus given intermittently for 56days partially rescued mTORC1 sensitivity to the drug but without inducing autophagy. The failure to induce autophagy following long-term everolimus administration was due to uncoupling of the mTORC1 substrate unc-51 like autophagy activating kinase 1.Our data encourage the use of intermittent everolimus regimens to prevent tolerance and to extend its activity.

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