Publications by authors named "Maike Scherf-Clavel"

17 Publications

  • Page 1 of 1

The role of pharmacogenetics in the treatment of anxiety disorders and the future potential for targeted therapeutics.

Expert Opin Drug Metab Toxicol 2021 Oct 15:1-12. Epub 2021 Oct 15.

Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.

Introduction: Anxiety disorders (AD) are among the most common mental disorders worldwide. Pharmacotherapy, including benzodiazepines, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants is currently based on 'trial-and-error,' and is effective in a subset of patients or produces partial response only. Recent research proposes that treatment response and tolerability of the drugs are associated with genetic factors.

Areas Covered: In the present review, we provide information on pharmacogenetics (PGx) in AD, including pharmacokinetic and pharmacodynamic genes. Moreover, we discuss the future potential of PGx for personalized treatment.

Expert Opinion: In psychiatry, PGx testing is still in its infancy, especially in the treatment of AD. As of today, implementation in clinical routine is recommended only for CYP2D6 and CYP2C19, mainly in terms of safety of treatment and potentially of treatment outcome in general. However, the evidence for PGx testing addressing pharmacodynamics for specific AD is limited to date. Nevertheless, PGx may develop into a valuable and promising tool to improve therapy in AD, but there is a need for more research to fully exploit its possibilities. Future perspectives include research into single genes, polygenic risk scores, and pharmacoepigenetics to provide targeted therapy.
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http://dx.doi.org/10.1080/17425255.2021.1991912DOI Listing
October 2021

Patients with higher vitamin D levels show stronger improvement of self-reported depressive symptoms in psychogeriatric day-care setting.

J Neural Transm (Vienna) 2021 Aug 25;128(8):1233-1238. Epub 2021 Jul 25.

Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany.

Depression is a common psychiatric disorder among geriatric patients that decreases the quality of life and increases morbidity and mortality. Vitamin D as a neuro-steroid hormone might play a role in the onset and treatment of depression. In the present study, the association between depressive symptoms and vitamin D concentration in serum was evaluated. 140 patients of a psychogeriatric day-care unit were included. The geriatric depression scale (GDS) and the Hamilton depression rating scale (HDRS) were assessed at the beginning and end of treatment, GDS scores additionally 6 weeks after discharge from the day-care unit. Vitamin D levels were measured at the beginning of the treatment, routinely. Patients with levels below 30 µg/L were treated with 1000 IU vitamin D per day. There was no association between the severity of depressive symptoms and the concentration of vitamin D at the beginning of the treatment. Patients with higher vitamin D levels showed a stronger decline of depressive symptoms measured by the GDS during their stay in the day-care unit. We provide evidence that vitamin D serum levels might influence antidepressant therapy response in a geriatric population. Prospective studies are necessary to determine which patients may profit from add-on vitamin D therapy.
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http://dx.doi.org/10.1007/s00702-021-02385-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321983PMC
August 2021

Antipsychotics in routine treatment are minor contributors to QT prolongation compared to genetics and age.

J Psychopharmacol 2021 Sep 28;35(9):1127-1133. Epub 2021 Mar 28.

Center for Mental Health, University Hospital of Würzburg, Würzburg, Germany.

Background: Drug-induced prolongation of cardiac repolarization limits the treatment with many psychotropic drugs. Recently, the contribution of polygenic variation to the individual duration of the QT interval was identified.

Aims: To explore the interaction between antipsychotic drugs and the individual polygenic influence on the QT interval.

Methods: Retrospective analysis of clinical and genotype data of 804 psychiatric inpatients diagnosed with a psychotic disorder. The individual polygenic influence on the QT interval was calculated according to the method of Arking et al.

Results: Linear regression modelling showed a significant association of the individual polygenic QT interval score (ß = 0.176, < 0.001) and age (ß = 0.139, < 0.001) with the QTc interval corrected according to Fridericia's formula. Sex showed a nominal trend towards significance (ß = 0.064, = 0.064). No association was observed for the number of QT prolonging drugs according to AZCERT taken. Subsample analysis ( = 588) showed a significant association of potassium serum concentrations with the QTc interval (ß = -0.104, = 0.010). Haloperidol serum concentrations were associated with the QTc interval only in single medication analysis ( = 26, ß = 0.101, = 0.004), but not in multivariate regression analysis. No association was observed for aripiprazole, clozapine, quetiapine and perazine, while olanzapine and the sum of risperidone and its metabolite showed a negative association.

Conclusions: Individual genetic factors and age are main determinants of the QT interval. Antipsychotic drug serum concentrations within the therapeutic range contribute to QTc prolongation on an individual level.
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http://dx.doi.org/10.1177/02698811211003477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436313PMC
September 2021

Dose-Corrected Serum Concentrations and Metabolite to Parent Compound Ratios of Venlafaxine and Risperidone from Childhood to Old Age.

Pharmacopsychiatry 2021 May 8;54(3):117-125. Epub 2020 Dec 8.

Department Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.

Objective: Comparative pharmacokinetic data about the antidepressant venlafaxine (VEN) and the antipsychotic drug risperidone (RIS) over the lifespan and especially in children and adolescents is lacking. This is the first cross-sectional study that aimed to investigate differences in dose-corrected serum concentrations (CDs) and metabolite to parent compound ratios (MPRs) of VEN and RIS across the lifespan.

Methods: Patients treated with VEN and RIS at the University Hospital of Würzburg, Germany were included in the study. Serum level determinations were performed during clinical routine care. Patients with CYP2D6 influencing co-medication were excluded from analyses.

Results: In 953 patients (12-93 years) treated with VEN and 552 patients (7-92 years) treated with RIS, children/adolescents (<18 years) showed 11% and 19%, and 44% and 42% lower CDs of the active moieties (CDs) of VEN and RIS than adults and elderly (≥60 years) (Kruskal-Wallis tests; p ≤ 0.001). However, when CDs were normalized to body weight, a different pattern emerged. Gender differences, with higher CDs in females were present in adults and elderlies but not in children/adolescents. No gender- or age-dependent difference in MPRs was found; however, 80% of MPRs of RIS in children/adolescents were below the range of "normal" CYP2D6 function for adults.

Conclusions: We suggest a higher clearance as a reason for lower CDs of VEN and RIS in children/adolescents compared to adults/elderlies. Metabolism of VEN or RIS by CYP2D6, characterized by MPRs, was not associated with age. However, MPRs of RIS were lower in children/adolescents, possibly due to a higher renal clearance of 9-OH-risperidone.
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http://dx.doi.org/10.1055/a-1302-8108DOI Listing
May 2021

Impact of Body Mass Index on Serum Concentrations of Antidepressants and Antipsychotics.

Ther Drug Monit 2021 04;43(2):286-291

Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany.

Background: Rates of overweight and obesity are higher in patients suffering from psychiatric disorders than in the general population. Body composition and enzyme functions are affected by overweight, and consequently, the pharmacokinetics of drugs may vary in overweight patients. Thus, overweight and obesity are important factors in psychiatric disorders and their treatment. This analysis aimed to investigate the impact of body mass index (BMI) on serum concentrations of the antidepressant drugs amitriptyline, doxepin, escitalopram, mirtazapine, and venlafaxine, and the antipsychotic drugs clozapine, quetiapine, and risperidone, taking into account the following confounding parameters: age, sex, and smoking habit.

Methods: Inpatients and outpatients (N = 1657) who took at least one of the target drugs were included in this retrospective analysis. Serum concentrations of the target drugs and their metabolites were determined at the Department of Psychiatry, Psychosomatics, and Psychotherapy of the University Hospital of Würzburg during routine therapeutic drug monitoring (January 2009-December 2010), which was performed in the morning (trough level) at steady state.

Results: Dose-corrected serum concentrations (CD) of the active moiety of doxepin and venlafaxine and of O-desmethylvenlafaxine were negatively associated with BMI (partial Pearson correlation, R = -0.267, P = 0.002; R = -0.206, P ≤ 0.001; R = -0.258, P ≤ 0.001), and the CDs were different in normal weight, overweight, and obese patients (analysis of covariance, P = 0.004, P < 0.001, P ≤ 0.001). No association was found between BMI and serum concentrations of amitriptyline, escitalopram, mirtazapine, clozapine, quetiapine, and risperidone.

Conclusions: In obese patients, higher doses of doxepin and venlafaxine are necessary to achieve similar serum concentrations as in normal weight patients and to avoid treatment-resistant depression.
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http://dx.doi.org/10.1097/FTD.0000000000000812DOI Listing
April 2021

Higher venlafaxine serum concentrations necessary for clinical improvement? Time to re-evaluate the therapeutic reference range of venlafaxine.

J Psychopharmacol 2020 10 16;34(10):1105-1111. Epub 2020 Jul 16.

Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany.

Background: The therapeutic reference range for venlafaxine in antidepressant treatment has been defined as 100 to 400 ng/mL. However, in an everyday setting active moiety concentrations above the therapeutic reference range were often reported.

Aim: The aim of this study was to re-evaluate the therapeutic reference range of venlafaxine.

Methods: In-patients (⩽60 years) with major depressive episodes receiving antidepressant monotherapy with venlafaxine during routine clinical treatment were included in this observational study. Depressive symptom severity was evaluated on a weekly basis using the Hamilton Depression Rating Scale (HAMD-21), and therapeutic drug monitoring analyses were performed. Resting electrocardiograms were analyzed in week 3, week 5 and week 7 of study participation.

Results: Clinical improvement from baseline to week 4 was significantly associated with increasing serum concentrations of the active moiety of venlafaxine ( = 23, Pearson correlation, = 0.009), but not with the dose of venlafaxine. Patients achieving remission showed significantly higher serum concentrations than patients achieving response/non-response (Kruskal-Wallis test, = 0.019). Moreover, in patients with serum concentrations above 400 ng/mL time to remission and time to response was significantly shorter than in patients with concentrations below 400 ng/mL (Mantel-COX test, = 0.001; = 0.010). QTc time was below the upper limit of a normal QTc time (450 ms) for all patients.

Conclusion: The serum concentration of the active moiety and not the dose determined the effect of venlafaxine. Shorter remission times without ECG alterations in patients with serum concentrations above the therapeutic reference range suggest a re-evaluation of the therapeutic reference range for venlafaxine in larger studies.
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http://dx.doi.org/10.1177/0269881120936509DOI Listing
October 2020

Therapeutic Drug Monitoring of Antidepressants for the Treatment of Chronic Musculoskeletal Pain With and Without Depression.

Ther Drug Monit 2020 12;42(6):893-901

Anesthesiology, Center for Interdisciplinary Pain Medicine, University Hospital of Würzburg, Würzburg, Germany.

Background: Antidepressants are recommended for the treatment of chronic musculoskeletal pain; however, target serum concentrations based on therapeutic drug monitoring (TDM) have not been established. Therefore, the authors analyzed routine care TDM data of antidepressants in patients with chronic pain with and without depression in terms of treatment outcomes in an interdisciplinary multimodal pain treatment (IMPT) program.

Methods: Patients with chronic musculoskeletal pain and TDM for amitriptyline (n = 45) or duloxetine (n = 30) were retrospectively included. The German pain questionnaire for pain intensity and the Depression Anxiety Stress scale were applied at T0 and at the end of the IMPT program (T1). A relief of pain intensity score ≥2 was considered as a positive outcome. Comorbid depression was diagnosed based on ICD-10 criteria. Serum concentrations of antidepressants were measured for routine clinical care TDM.

Results: After IMPT, stress improved in all subgroups, and depressive symptoms improved only in the duloxetine group. Overall, 40% and 27% of patients in the amitriptyline and duloxetine subgroup, respectively, were responders in terms of maximum pain score relief. Responders with comorbid depression were treated with a dose that led to a 1.7-fold higher serum concentration of the active moiety of amitriptyline (amitriptyline + nortriptyline) compared with nonresponders. Similarly, a 2.3-fold higher serum concentration was observed in depressed responders than in nondepressed responders (at minimum 131.5 ng/mL).

Conclusions: Dosing of antidepressants for chronic pain relief should specifically take comorbid depression into account. TDM may provide better outcomes of pain relief in an IMPT setting in patients with comorbid depression.
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http://dx.doi.org/10.1097/FTD.0000000000000783DOI Listing
December 2020

Drug-Drug Interactions Between Lithium and Cardiovascular as Well as Anti-Inflammatory Drugs.

Pharmacopsychiatry 2020 Sep 27;53(5):229-234. Epub 2020 Apr 27.

Department of Psychiatry, Psychosomatics and Psychotherapy, Centre of Mental Health, University Hospital of Würzburg, Würzburg, Germany.

Introduction: Lithium is the gold standard in treating bipolar affective disorders. As patients become increasingly older, drug-drug interactions leading to decreased excretion of lithium represent a key issue in lithium safety. As no study considered the effect of comedications on lithium serum concentration in combination, we aimed to quantify the impact of drugs affecting renal blood flow and function and thus potentially interacting drugs (diuretics, ACE inhibitors, AT1 antagonists, and non-steroidal anti-inflammatory drugs) on lithium serum levels in addition to age, sex, and sodium and potassium serum levels as well as renal function.

Methods: Retrospective data of lithium serum levels were analyzed in 501 psychiatric inpatients (2008-2015) by means of linear regression modelling.

Results: The number of potentially interacting drugs was significantly associated with increasing serum levels of lithium in addition to the established factors of age, renal function, and sodium concentration. Additionally, absolute lithium levels were dependent on sex, with higher values in females. However, only NSAIDs were identified to increase lithium levels independently.

Discussion: Routine clinical practice needs to focus on drugs affecting renal blood flow and function, especially on NSAIDs as over-the-counter medication that may lead to an increase in lithium serum concentration. To prevent intoxications, clinicians should carefully monitor the comedications, and they should inform patients about possible intoxications due to NSAIDs.
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http://dx.doi.org/10.1055/a-1157-9433DOI Listing
September 2020

Extent of cortisol suppression at baseline predicts improvement in HPA axis function during antidepressant treatment.

Psychoneuroendocrinology 2020 04 26;114:104590. Epub 2020 Jan 26.

Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany; Interdisciplinary Center for Clinical Research, University of Würzburg, Josef-Schneider-Strasse 2, 97080, Würzburg, Germany; Comprehensive Heart Failure Center, University Hospital of Würzburg, Am Schwarzenberg 15, Würzburg, 97080, Germany.

Background: A dysregulation in the hypothalamic-pituitary-adrenal (HPA)-axis function has been repeatedly observed in major depressive disorders (MDD). Normalization of this dysregulation, i.e. of cortisol suppression after glucocorticoid receptor (GR)-stimulation, may be mandatory for clinical remission in some patient subgroups. However, there are no biological measures applied in the clinical setting to identify patient subgroups with HPA axis alterations.

Objective: We aimed to define a suppression index of cortisol concentrations before and after GR stimulation with dexamethasone to predict the variability in improvement of HPA axis activity during antidepressant treatment.

Methods: A modified dexamethasone suppression test (mDST) was performed with blood withdrawal for cortisol and ACTH measurement before and 3 h after 1.5 mg dexamethasone intake at 18:00 in two cohorts of depressed patients treated in a naturalistic setting. The discovery sample consisted of 106 patients, the replication sample of 117 patients. The suppression index was defined as cCORTpreDEXcCORTpostDEX.

Results: The baseline suppression index explained 27.4 % of the variance in changes of HPA axis activity before and after treatment with antidepressants. Age, cCORTpreDEXcACTHpreDEX at baseline and sex explained further variance up to 56.2 % (stepwise linear regression, p = 7.8e). A threshold of the suppression index at baseline was determined by ROC analysis and revealed, that only patients with a maximum index of 2.32 achieved a normalization of the HPA axis activity after antidepressant treatment. In the replication sample, the threshold was 2.86. However, the estimated suppression index was not associated with treatment response.

Conclusion: For the first time, by establishing a short-term suppression index of cortisol before and after GR-stimulation a threshold could be identified to predict improvement of HPA axis activity during antidepressant therapy. After replication in further studies this index may help to identify patients who benefit from a specific treatment that targets components of the HPA axis in the future.
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http://dx.doi.org/10.1016/j.psyneuen.2020.104590DOI Listing
April 2020

Nortriptyline serum concentration as a predictor for cardiac risk in amitriptyline-treated patients.

Eur J Clin Pharmacol 2020 Jan 23;76(1):73-80. Epub 2019 Oct 23.

Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany.

Purpose: Tricyclic antidepressants have been shown to affect electrocardiogram (ECG) parameters, but there is limited evidence in relation to the serum concentrations. Therefore, we aimed to evaluate a prediction of cardiac risk in amitriptyline- and doxepin-treated patients by serum concentrations.

Patients And Methods: The association between serum concentrations of amitriptyline (n = 100) and doxepin (n = 71) and ECG parameters was retrospectively examined using linear regression analysis. Mann-Whitney U tests were applied to evaluate differences in QTc intervals in patients with serum concentrations above and below the upper limit of the therapeutic reference range, as well as the alert level of each target drug.

Results: The sum serum concentration of amitriptyline and the nortriptyline serum concentration were significantly associated with an increased PQ interval (p = 0.020, p = 0.007), as well as with increased QTcB (p = 0.012, p < 0.001) and QTcF intervals (p = 0.025, p < 0.001). The nortriptyline concentration was significantly associated with the QRS interval (p = 0.003). In patients with active moiety concentrations above the alert level (300 ng/ml) and nortriptyline concentrations above the reference range (170 ng/ml), the QTcB interval was significantly prolonged (p = 0.032, p = 0.007). No significant association with any ECG parameter was detected for doxepin serum concentrations.

Conclusion: The effect of amitriptyline on ECG parameters may be explained by nortriptyline alone. Accordingly, with increasing nortriptyline concentrations, the potential risk for an atrioventricular block, a bundle branch block, and prolongation of QTc interval may increase significantly.
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http://dx.doi.org/10.1007/s00228-019-02766-2DOI Listing
January 2020

Smoking Is Associated With Lower Dose-Corrected Serum Concentrations of Escitalopram.

J Clin Psychopharmacol 2019 Sep/Oct;39(5):485-488

From the Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany.

Background: Tobacco smoking rates in depressive patients are higher compared with the general population. Smoking was demonstrated to accelerate the metabolism of different drugs metabolized by CYP1A2, but possibly also by CYP2C19 and CYP3A4. The principle aim of the present investigation from 2015 to 2018 was to determine the differences in the pharmacokinetics of escitalopram between smokers and nonsmokers.

Methods: A group of nonsmokers (n = 88) was compared with smokers (n = 36), both receiving escitalopram, using the Mann-Whitney U test. Linear regression analysis was used to account for the impact of escitalopram dose, age, and sex in addition to smoking on the steady-state serum concentration of escitalopram.

Results: Smokers received by mean 17.6% higher doses of escitalopram (P = 0.026) but showed 31.9% lower serum concentrations (P = 0.031). To control for confounders, linear regression analysis showed that dose (P < 0.001), sex (P = 0.03), and smoking tobacco (P = 0.027) did significantly influence serum concentrations of escitalopram with higher levels in women and nonsmokers.

Conclusions: Notwithstanding higher daily doses, smokers had significantly lower serum concentrations of escitalopram. In concordance with previous results, besides CYP1A2, a possible induction of CYP2C19 and CYP3A4 by tobacco smoke, resulting in lower serum concentrations of escitalopram in smokers than in nonsmokers, is suggested. Therefore, to provide personalized therapy, clinicians should consider smoking status and inform patients on the interactions of smoking and escitalopram metabolism.
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http://dx.doi.org/10.1097/JCP.0000000000001080DOI Listing
January 2020

Determination of hydroxybupropion in human serum for routine therapeutic drug monitoring in psychiatry: A tool for dose-individualization in treatment with bupropion.

Biomed Chromatogr 2019 Oct 17;33(10):e4609. Epub 2019 Jun 17.

Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.

Therapeutic drug monitoring (TDM) has become a clinical routine in psychiatry. Nevertheless, for bupropion there is only one method available that is suitable for routine use. However, it involves a complex sample clean-up. Owing to the instability of bupropion in serum, the main and active metabolite hydroxybupropion was chosen as the target substance. Therefore, a simple and robust high-performance liquid chromatography method for the quantification of hydroxybupropion in serum was developed and validated. A volume of 30 μL serum was used for easy sample clean-up, based on protein precipitation with acetonitrile followed by online solid-phase extraction. As hydroxybupropion was present in high serum concentrations, UV detection was possible. Owing to the commonly available instrumentation, the method could easily be integrated in routine TDM. The newly developed method was validated following the guidelines for bioanalytical method validation of the European Medicines Agency and US Food and Drug Administration. The lower limit of quantification was 100 ng/mL (0.391 μm) and linearity was shown between 100 and 2500 ng/mL. Intraday and interday precision ranged from 1.17 to 6.79% and from 6.07 to 9.41%, respectively. Intraday and interday accuracy ranged from 89.97 to 110.86% and from 95.05 to 101.2%. The method was shown to be selective, accurate and precise. Additionally, the method was successfully implemented in the therapeutic drug monitoring laboratory of the Department of Psychiatry, Psychosomatics and Psychotherapy at the University Hospital of Würzburg, Germany. Six months of routine analysis showed a rather low correlation between applied dose and serum concentration and therefore the necessity of TDM for dose-individualization in the treatment with bupropion.
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http://dx.doi.org/10.1002/bmc.4609DOI Listing
October 2019

Pathological Concentration of C-reactive Protein is Correlated to Increased Concentrations of Quetiapine, But Not of Risperidone, Olanzapine and Aripiprazole in a Naturalistic Setting.

Pharmacopsychiatry 2020 Jan 26;53(1):30-35. Epub 2019 Mar 26.

Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany.

Introduction: Infections can alter drug clearance, but the impact of inflammation-induced changes is still not well known. The aim of the investigation was to examine the effect of pathological C-reactive protein (CRP) values (≥0.5 mg/dL) and leukocyte count on the metabolism of 4 different atypical antipsychotics.

Methods: Steady-state serum concentrations of individual patients under therapy with risperidone (n=45), aripiprazole (n=30), olanzapine (n=24), and quetiapine (n=166) were retrospectively analyzed during a period of inflammation by Spearman's Rho correlation analysis. Mann-Whitney U test was applied for comparison of patients with serum concentrations above and below the upper limit of the therapeutic reference range of each target drug with regard to CRP concentration and leukocyte count. Linear regression analysis was applied to correct for confounding parameters age and sex.

Results: Pathological concentrations of CRP were significantly associated with elevated values of C/D of quetiapine (n=166, Spearman's Rho: r=0.269, p<0.001; linear regression: p<0.001). Among patients with quetiapine serum concentrations below 500 ng/mL, CRP concentrations were significantly (p=0.006) lower compared to patients with quetiapine concentrations above 500 ng/mL. A trend for a positive correlation between CRP and serum concentration was found for olanzapine (n=24, Spearman's Rho: r=0.385, p=0.063; linear regression: p=0.086).

Conclusion: During a period of inflammation in patients taking quetiapine, according to our results, attention in dosing strategies is required to prevent toxic plasma concentrations.
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http://dx.doi.org/10.1055/a-0869-8053DOI Listing
January 2020

Dried blood spot testing for estimation of renal function and analysis of metformin and sitagliptin concentrations in diabetic patients: a cross-sectional study.

Eur J Clin Pharmacol 2019 Jun 31;75(6):809-816. Epub 2019 Jan 31.

Institut für Pharmazie und Lebensmittelchemie, Universität Würzburg, Am Hubland, 97074, Würzburg, Germany.

Purpose: Dried blot spot (DBS) analysis of drugs or clinical parameters offers many advantages. We investigated the feasibility of using DBS for analysis of anti-diabetic drugs concomitantly with the estimated creatinine clearance (Cl).

Methods: The cross-sectional study involved physicians in an enabling analysis with 70 diabetic patients and community pharmacists in a field investigation with 84 participants. All 154 DBS samples were analyzed for creatinine, metformin, and sitagliptin.

Results: The diabetic patients revealed of a wide range of age (32-88 years), BMI values (19.8-54.7 kg/m), and extent of polypharmacotherapy (1-21 drugs). A correlation factor to convert capillary blood creatinine from DBS into plasma concentrations was determined. Patients' Cl ranged from 21.6-155.9 mL/min. The results indicated statistically significant correlations (p < 0.05) between the use of two or three particular drug classes (diuretics, NSAIDs, renin-angiotensin system blockers) and a decreased renal function. DBS concentrations of metformin ranged between 0.23-4.99 μg/mL. The estimated elimination half-life (t ½) of metformin was 11.9 h in patients with a Cl higher than 60 mL/min and 18.5 h for diabetics with lower Cl. Sitagliptin capillary blood concentrations ranged between 11.12-995.6 ng/mL. Calculated t ½ of sitagliptin were 8.4 h and 13.0 h in patients with a Cl above and below 60 mL/min, respectively.

Conclusions: DBS allow for the analysis of concentrations of predominantly renally eliminated drugs and community pharmacists can provide a valuable contribution to DBS sampling.
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http://dx.doi.org/10.1007/s00228-019-02637-wDOI Listing
June 2019

Analysis of smoking behavior on the pharmacokinetics of antidepressants and antipsychotics: evidence for the role of alternative pathways apart from CYP1A2.

Int Clin Psychopharmacol 2019 03;34(2):93-100

Department of Psychiatry, Psychosomatics and Psychotherapy.

Smoking is common among psychiatric patients and has been shown to accelerate the metabolism of different drugs. We aimed to determine the effect of smoking on the serum concentrations of psychopharmacological drugs in a naturalistic clinical setting. Dose-corrected, steady-state serum concentrations of individual patients were analyzed retrospectively by linear regression including age, sex, and smoking for amitriptyline (n=503), doxepin (n=198), mirtazapine (n=572), venlafaxine (n=534), clozapine (n=106), quetiapine (n=182), and risperidone (n=136). Serum levels of amitriptyline (P=0.038), clozapine (P=0.02), and mirtazapine (P=0.002) were significantly lower in smokers compared with nonsmokers after correction for age and sex. In addition, the ratios of nortriptyline/amitriptyline (P=0.001) and nordoxepin/doxepin (P=0.014) were significantly higher in smokers compared with nonsmokers. Smoking may not only induce CYP1A2, but may possibly also affect CYP2C19. Furthermore, CYP3A4, UGT1A3, and UGT1A4 might be induced by tobacco smoke. Hence, a different dosing strategy is required among smoking and nonsmoking patients. Nevertheless, the clinical relevance of the results remained unclear.
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http://dx.doi.org/10.1097/YIC.0000000000000250DOI Listing
March 2019

Analysis of metformin, sitagliptin and creatinine in human dried blood spots.

J Chromatogr B Analyt Technol Biomed Life Sci 2015 Aug 20;997:218-28. Epub 2015 Jun 20.

Universität Würzburg, Institut für Pharmazie und Lebensmittelchemie, Würzburg, Germany.

For analysis of the anti-diabetic drugs metformin and sitagliptin and the renal clearance marker creatinine in the same human dried blood spot (DBS) extract two liquid chromatography methods employing HPLC/UV and LC-ESI-MS/MS have been developed and validated. An accurate volume of 40μL blood was spotted on a sampling paper which was extracted using 90% acetonitrile with 10% formic acid. The new methods were shown to be selective, accurate and precise. The validated ranges were 0.2-5μg/mL for metformin, 1.5-15μg/mL for creatinine and 3-500ng/mL for sitagliptin. Since drug analysis in DBS determines whole blood concentrations as opposed to the typically used plasma levels the partition ratios between human plasma and blood cells, c(P)/c(BC), were elucidated in vitro to gain insight into the significance of blood cells as compartment of distribution for both compounds. The c(P)/c(BC) was found to be 4.65±0.73 for metformin and 5.58±0.98 for sitagliptin. While an accumulation of metformin in erythrocytes was already known we now present the first evidence that sitagliptin distributes into human blood cells. The analytical methods were also successfully applied to authentic capillary blood samples from two diabetic patients regularly taking a combination of metformin and sitagliptin. Both samples revealed analyte trough concentrations well above the lower limit of quantification of the respective compounds. Therefore, the present study offers a methodological basis for the DBS analysis of metformin and sitagliptin in relation to the patients' creatinine concentration.
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http://dx.doi.org/10.1016/j.jchromb.2015.06.014DOI Listing
August 2015

Application of gas pycnometry for the density measurement of freeze-dried products.

J Pharm Sci 2013 Nov 9;102(11):4087-99. Epub 2013 Sep 9.

Freeze Drying Focus Group (FDFG), Division of Pharmaceutics, D-91058 University of Erlangen, Erlangen, D-91058, Germany.

Gas pycnometry is applied to determine the density of solid materials. The analysis of lyophilisates is particularly challenging because of their porous structure. In this study, the density of raw materials and freeze-dried products was determined using different pycnometric methodologies and gases [helium (He), nitrogen (N2 ), sulfur hexafluoride]. The number of purges was set to 60 independent of the gas used. Intact and ground lyophilisates were examined, and major differences were found between use of He and N2 . For example, the density of sucrose lyophilisates measured using He remained almost constant before (1.51 g/cm(3) ) and after (1.52 g/cm(3) ) grinding. In contrast, the density of a sucrose lyophilisate before grinding determined with N2 was 1.33 g/cm(3) . On the basis of μCT and scanning electron microscopy pictures, it appears likely that the majority of pores are interconnected, with only a small fraction of closed pores. Helium is able to penetrate deep into the freeze-dried matrix and is supposedly absorbed by the material. The N2 molecules were not able to penetrate closed pores; therefore, the skeletal density of an intact lyophilisate was determined. Reproducibility of the established method was verified, and freeze-dried orally disintegrating tablets of different compositions were analyzed.
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http://dx.doi.org/10.1002/jps.23723DOI Listing
November 2013
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