David Czock

Universität Heidelberg, Heidelburg, Baden-Württemberg, Germany

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Publications (89)176.05 Total impact

  • Frieder Keller · David Czock

    No preview · Article · Sep 2015 · Clinical nephrology
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    ABSTRACT: Background Recommendations on drug dose adjustment in patients with renal impairment may vary between the references. It is often unknown which approach the dosing schemes were based on and what drug exposure is likely to be achieved. Objective To develop a simple method to evaluate recommended dosing schemes for patients with renal impairment, to apply this method to selected antibacterial drugs in order to evaluate expected drug concentrations using dosing schemes recommended for patients with severe infections, and to evaluate the expected consequences. Setting This was a theoretical study, which was based on data from published clinical trials. Methods Clinically established dosing schemes for 46 antibacterial drugs, as recommended for patients with renal impairment in the Summary of Product Characteristics, were analysed using a newly developed graphical method. Consistency of the dosing schemes with two general dose adjustment rules, the proportional rule and the eliminated fraction rule, was determined and drug exposure was predicted. Main outcome measure Predicted drug exposure. Consistency of recommended dosing schemes with the general dose adjustment rules. Results Only 30 % of the recommended dosing schemes were associated with similar average concentrations as expected in patients with normal renal function (44 % were associated with higher and 26 % with lower concentrations). The highest median exposure was found in beta-lactams (170 %, range 58-443 %, for creatinine clearance of
    No preview · Article · May 2015
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    D. Czock · F. Keller
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    ABSTRACT: Bei Anwendung renal eliminierter Arzneimittel kann es bei Patienten mit Niereninsuffizienz zu einer übermäßigen Akkumulation mit hohen Konzentrationen kommen, sodass eine Anpassung der Dosierung erwogen werden sollte, um konzentrationsabhängige unerwünschte Arzneimittelwirkungen zu vermeiden. Bei einer Dosisanpassung sollten Patientenfaktoren (z. B. Schwere des Infekts), Behandlungsfaktoren (z. B. Zeitpunkt der Dialyse, Membrantyp) und Arzneimittelfaktoren (z. B. Ausmaß der Abhängigkeit von der Nierenfunktion, Pharmakodynamik) berücksichtigt werden. Je nach gewählter Dosisanpassung (Reduktion der Einzeldosis, Verlängerung des Dosierungsintervalls) ist mit unterschiedlichen Konzentrationsverläufen zu rechnen. Ein therapeutisches Drug-Monitoring kann helfen, die individuell beste Dosierung für einen Patienten zu finden.
    Preview · Article · May 2015 · Der Nephrologe
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    ABSTRACT: Electronic alerts are often ignored by physicians, which is partly due to the large number of unspecific alerts generated by decision support systems. The aim of the present study was to analyze critical drug prescriptions in a university-based nephrology clinic and to evaluate the effect of different alerting strategies on the alert burden. In a prospective observational study, two advanced strategies to automatically generate alerts were applied when medication regimens were entered for discharge letters, outpatient clinic letters, and written prescriptions and compared to two basic reference strategies. Strategy A generated alerts whenever drug-specific information was available, whereas strategy B generated alerts only when the estimated glomerular filtration rate of a patient was below a drug-specific value. Strategies C and D included further patient characteristics and drug-specific information to generate even more specific alerts. Overall, 1012 medication regimens were entered during the observation period. The average number of alerts per drug preparation in medication regimens entered for letters was 0.28, 0.080, 0.019, and 0.011, when using strategy A, B, C, or D (P<0.001, for comparison between the strategies), leading to at least one alert in 87.5%, 39.3%, 13.5%, or 7.81 % of the regimens. Similar average numbers of alerts were observed for medication regimens entered for written prescriptions. The prescription of potentially hazardous drugs is common in patients with renal impairment. Alerting strategies including patient and drug-specific information to generate more specific alerts have the potential to reduce the alert burden by more than 90 %. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    No preview · Article · Apr 2015 · Journal of the American Medical Informatics Association
  • David Czock · Claudia Sommerer

    No preview · Article · Mar 2015 · Dialyse aktuell

  • No preview · Conference Paper · Feb 2015
  • Frieder Keller · Ulla Ludwig · David Czock
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    ABSTRACT: Introduction: In the TREAT and RED-HF trials, patients who received a high darbepoetin dose had an increased risk of adverse events. To find an explanation, the published literature was analyzed on the pharmacokinetics and pharmacodynamics of darbepoetin. Areas covered: Based on the sigmoid Emax model, the concentration producing 50% of the maximum erythropoietin effect is reported as CE50 = 0.41 ng/ml and the Hill coefficient as H = 3.0 for darbepoetin. Accordingly, a pharmacodynamics-based threshold concentration can be estimated with CE05 = 0.153 ng/ml producing 5% of Emax and a ceiling concentration with CE95 = 1.098 ng/ml producing 95% of Emax, respectively. Expert opinion: Darbepoetin trough levels should not be less than the threshold concentration but peak levels above the ceiling concentration could be associated with an increased risk of adverse events. The time span associated with the concentration fluctuation between the ceiling and the threshold concentration is estimated with 236 h (= 2.84 times elimination half-life of 83 h) and shorter than the 336 h when dosing every other week. According to such time-dependent pharmacodynamics, a weekly dosing regimen might be more effective and associated with less adverse events than higher doses every other week in patients with suboptimal response to a normal darbepoetin dose.
    No preview · Article · Dec 2014 · Expert Opinion on Drug Metabolism & Toxicology
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    ABSTRACT: Drug interactions with immunosuppressive drugs are a major problem of protease inhibitor based antiviral triple therapy of Hepatitis C virus reinfection after liver transplantation. In this retrospective cohort study we analyzed biomarkers of immunosuppressive effects of cyclosporine A (CsA) by quantifying nuclear factor of activated T cells (NFAT)–regulated gene expression during telaprevir therapy in five liver transplant patients. Furthermore, dose adjustment and blood concentrations of CsA as well as the clinical course were analyzed.We observed a clear impact of telaprevir not only on dose and blood concentrations but also on immunosuppressive effects of CsA. Despite apparently adequate CsA trough concentrations, CsA peak concentrations decreased to 68 [44-90] %. This was associated with a 1.9 [1.6-4.1]-fold increase in the residual gene activity of NFAT regulated genes, which indicates a reduced immunosuppressive activity of CsA during telaprevir co-medication. The median [min–max] dose of CsA was reduced to 25 [16-48] % and 31 [22-64] % after one and two weeks. CsA drug-clearance was reduced to 39 [31-49] %.We report excellent antiviral efficacy. At the end of observation, all patients were HCV RNA negative (one patient 18 weeks, one patient 12 weeks and three patients 4 weeks after the end of therapy). Safety was acceptable with mild acute rejection and reactivation of cytomegalovirus as the most serious adverse events. One patient with histological proven recurrent cholestatic hepatitis before therapy underwent retransplantation during the course of antiviral therapy.In conclusion, immunomonitoring of NFAT-regulated gene expression indicated reduced immunosuppressive activity of CsA during antiviral therapy with telaprevir in our cohort of liver transplant patients. Thus, immunosuppressive effects of CsA may be overestimated when looking only on trough concentrations during comedication with protease inhibitors or other strong CYP3A inhibitors. Immunomonitoring of NFAT-regulated gene expression could therefore help to prevent over- or under-immunosuppression. Liver Transpl , 2014. © 2014 AASLD.
    No preview · Article · Sep 2014 · Liver Transplantation
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    ABSTRACT: Purpose Clinical decision support systems (CDSS) may potentially improve prescribing quality, but are subject to poor user acceptance. Reasons for alert overriding have been identified and counterstrategies have been suggested; however, poor alert specificity, a prominent reason of alert overriding, has not been well addressed. This paper aims at structuring modulators that determine alert specificity and estimating their quantitative impact on alert burden. Methods We developed and summarized optimizing strategies to guarantee the specificity of alerts and applied them to a set of 100 critical and frequent drug interaction (DDI) alerts. Hence, DDI alerts were classified as dynamic, i.e. potentially sensitive to prescription-, co-medication-, or patient-related factors that would change alert severity or render the alert inappropriate compared to static, i.e. always applicable alerts not modulated by cofactors. Results Within the subset of 100 critical DDI alerts, only 10 alerts were considered as static and for 7 alerts, relevant factors are not generally available in today's patient charts or their consideration would not impact alert severity. The vast majority, i.e. 83 alerts, might require a decrease in alert severity due to factors related to the prescription (N = 13), the co-medication (N = 11), individual patient data (N = 36), or combinations of them (N = 23). Patient-related factors consisted mainly of three lab values, i.e. renal function, potassium, and therapeutic drug monitoring results. Conclusion This paper outlines how promising the refinement of knowledge bases is in order to increase specificity and decrease alert burden and suggests how to structure knowledge bases to refine DDI alerting.
    No preview · Article · Apr 2014 · International Journal of Medical Informatics
  • Nicolas Hohmann · Gerd Mikus · David Czock
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    ABSTRACT: The number of newly reported psychoactive substances in Europe is now higher than ever. In order to evade legal restrictions, old and novel psychoactive substances from medical research and their derivatives are commonly mislabeled as "not for human consumption" and offered for sale on the Internet and elsewhere. Such substances are widely taken by young people as "club drugs." Their consumption must be considered in the differential diagnosis of psychiatric, neurological, cardiovascular, or metabolic disturbances of unclear origin in a young patient. Selective review of pertinent literature retrieved by a PubMed search, including publications by government-sponsored organizations. From 2010 to 2012, 163 substances were reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), mostly either synthetic cannabinoids (39.3%) or synthetic cathinones (16.6%). Synthetic cannabinoids alter mood and perception; intoxications cause agitation, tachy cardia, and arterial hypertension. Synthetic cathinones are hallucinogenic stimulants with predominantly cardiovascular and psychiatric side effects. Severe intoxications cause serotonin syndrome and potentially fatal rhabdomyolysis. Substances in either of these classes often escape detection in screening tests. Young persons who present with agitation and cardiovascular and/or psychiatric manifestations of unclear origin and whose drug screening tests are negative may be suffering from an intoxication with a novel psychoactive substance. Physicians should know the classes of such substances and their effects. Targeted toxicological analysis can be carried out in a toxicology laboratory or a facility for forensic medicine.
    No preview · Article · Feb 2014 · Deutsches Ärzteblatt International

  • No preview · Article · Jan 2014 · Zeitschrift für Gastroenterologie
  • D. Czock · F. Keller
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    ABSTRACT: Administration of drugs that are largely eliminated by the kidneys can lead to increased accumulation and high drug concentrations in patients with renal impairment. Thus, drug dose adjustment should be considered in order to avoid concentration-dependent side effects. Several factors should be considered when deciding on a drug dose adjustment, including patient-related factors (e.g. severity of the infection), treatment-related factors (e.g. timing and membrane type of hemodialysis), and drug-related factors (e.g. drug fraction eliminated by the kidneys, pharmacodynamics). Depending on the type of dose adjustment (reduction of doses, prolongation of dosing intervals) different concentration courses will be the result. Therapeutic drug monitoring can be useful to define the optimum dose and dosing interval in the individual patient.
    No preview · Article · Jan 2014
  • Frieder Keller · Bertram Hartmann · David Czock
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    ABSTRACT: A measure correlating the time course of the effect with the time course of concentrations could be helpful in drug dosing. We propose a new equation with explicit solutions for calculating the effect duration. A specific effect fraction is selected (fr) and the time of fractional effect duration (TED.fr) can be derived as a function of the elimination half-life by combining linear elimination kinetics with sigmoid effect dynamics. This new measure is applied to the example of sitagliptin, whose elimination half-life increases from 10.1 to 28.4 h in patients with kidney failure. Under normal multiple-dose conditions, the 24-h sitagliptin administration interval corresponds to a 0.90 time of fractional effect duration (TED.90). A dose reduction to one-fourth or 25 mg every 24 h is proposed for patients with kidney failure; this results in a TED.90 of 45 h, i.e. 21 h longer than the proposed 24-h administration interval (+88 %). The proportional dosing alternative of 100 mg every 96 h would result in a TED.90 of 64 h, which is 32 h less than the 96-h administration interval (-33 %). With a half dose of 50 mg and a doubled administration interval of 48 h, the TED.90 is 51 h in kidney failure, only 3 h longer than the latter administration interval (+6 %). We conclude that our general equation can be applied to rapidly calculate the specific time of effect duration for the different dose schedules.
    No preview · Article · Dec 2013 · European Journal of Drug Metabolism and Pharmacokinetics
  • René van Erp · David Czock · Frieder Keller

    No preview · Article · Dec 2013 · Der Klinikarzt
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    ABSTRACT: AimsImpaired liver function often necessitates drug dose adjustment to avoid excessive drug accumulation and adverse events, but a marker for the extent of the required adjustment is lacking. The aim of this study was to investigate whether Child-Pugh (CP) and model for end-stage liver disease (MELD) scores correlate with drug clearance. Methods Midazolam was used as a CYP3A probe and its pharmacokinetics were analyzed in 24 patients with mild to severe liver cirrhosis (n = 4, 10 and 10 with CP class A, B and C, respectively) and six patients without liver disease. ResultsBoth scores correlated well with unbound midazolam clearance (CLu), unbound midazolam fraction and half-life (all P < 0.01), whereas the unbound steady-state volume of distribution was not significantly changed. In patients with severe liver cirrhosis unbound midazolam clearance was only 14% of controls (CP C: CLu = 843 346 lh(-1), MELD 15: CLu = 805 +/- 474lh(-1), controls: CLu = 5815 +/- 2649lh(-1), P < 0.01). Conclusion The correlation with unbound midazolam clearance suggests that either score predicts the metabolic capacity of CYP3A, the most relevant drug metabolizing enzyme subfamily in humans.
    Full-text · Article · Jun 2013 · British Journal of Clinical Pharmacology
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    ABSTRACT: AimsMetformin pharmacokinetics depends on the presence and activity of membrane-bound drug transporters and may be affected by transport inhibitors. The aim of this study was to investigate the effects of trimethoprim on metformin pharmacokinetics and genetic modulation by organic cation transporter2 (OCT2) and multidrug and toxin extrusion1 (MATE1) polymorphisms. Methods Twenty-four healthy volunteers received metformin 500mg three times daily for 10 days and trimethoprim 200mg twice daily from day 5 to 10. Effects of trimethoprim on steady-state metformin pharmacokinetics were analysed. ResultsIn the population as a whole, trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54lh(-1) and renal metformin clearance from 31 to 21lh(-1), and prolonged half-life from 2.7 to 3.6h (all P < 0.01). This resulted in an increase in the maximal plasma concentration by 38% and in the area under the plasma concentration-time curve by 37%. In volunteers polymorphic for both OCT2 and MATE1, trimethoprim had no relevant inhibitory effects on metformin kinetics. Trimethoprim was associated with a decrease in creatinine clearance from 133 to 106mlmin(-1) (P < 0.01) and an increase in plasma lactate from 0.94 to 1.2mmoll(-1) (P = 0.016). Conclusions The extent of inhibition by trimethoprim was moderate, but might be clinically relevant in patients with borderline renal function or high-dose metformin.
    Full-text · Article · Jan 2013 · British Journal of Clinical Pharmacology

  • No preview · Article · Nov 2012 · Transplantation
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    ABSTRACT: : Developmental regulation of the pharmacodynamics of cyclosporin A (CsA) has been suggested by in vitro studies. However, these results have not yet been reproduced in the complexity of an in vivo immune system, because reliable biomarkers of CsA effects have not been available. : Gene expression of interleukin-2 (IL-2), interferon (IFN)-γ, and granulocyte macrophage colony stimulating factor (GM-CSF) in peripheral blood from stable pediatric (N = 31) and adult renal transplant recipients (N = 153) (age range 6.5-78 years) was measured by quantitative real-time polymerase chain reaction before (C0) and 2 hours (C2) after oral CsA intake. To control for the effect of varying CsA concentrations, an index was calculated as a measure of individual CsA sensitivity. : The CsA sensitivity of IL-2 gene expression in pediatric patients was 3.9% higher than in middle-aged adults and 5.2% higher than in seniors, indicating stronger immunosuppression at a given CsA blood concentration in younger patients. For the entire patient cohort, there was a statistically significant inverse correlation between the CsA sensitivity of IL-2 and chronological age (r = 0.142, P < 0.0001). Also, the CsA sensitivity of IFN-γ (r = 0.131, P < 0.0001) and GM-CSF (r = 0.036, P < 0.01) were inversely correlated with chronological age. Multiple linear regression analysis revealed that age was a highly significant (P = 0.0027) independent predictor for residual gene expression of IL-2, but not of IFN-γ and GM-CSF. : An increased sensitivity of IL-2 to suppression by CsA was found in pediatric renal transplant recipients in vivo compared with adults. Hence, there seems to be an effect of human development on CsA pharmacodynamics, which, besides the effect of age on pharmacokinetics, should also be considered for the design of treatment regimens of CsA and potentially other calcineurin inhibitors in the pediatric patient population.
    No preview · Article · Aug 2012 · Therapeutic drug monitoring
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    ABSTRACT: Since many drug targets and metabolizing enzymes are developmentally regulated, we investigated a potential comparable regulation of inosine 5'-monophosphate dehydrogenase (IMPDH) activity that has recently been advocated as a pharmacodynamic biomarker of mycophenolic acid (MPA) effects in the paediatric population. Since the field of pharmacodynamic monitoring of MPA is evolving, we also analyzed the response of IMPDH activity on MPA in children vs adolescents after renal transplantation. We analyzed IMPDH activity in peripheral blood mononuclear cells (PBMCs) in 79 healthy children aged 2.0-17.9 years in comparison to 106 healthy adults. Pharmacokinetic/pharmacodynamic profiles of MPA and IMPDH over 6 or 12 h after mycophenolate mofetil dosing were performed in 17 paediatric renal transplant recipients. IMPDH activity was measured by HPLC and normalized to the adenosine monophosphate (AMP) content of the cells, MPA plasma concentrations were measured by HPLC. Inosine 5'-monophosphate dehydrogenase activity displayed a high inter-individual variability (coefficient of variation 40.2%) throughout the entire age range studied. Median IMPDH did not differ significantly in healthy pre-school children (82 [range, 42-184] μmol/s/mol AMP), school-age children (61 [30-153]), adolescents (83 [43-154]) and healthy adults (83 [26-215]). Similar to adults, IMPDH activity in children and adolescents was inversely correlated with MPA plasma concentration. In conclusion, our data do not show a pronounced developmental regulation of IMPDH activity in PBMCs in the paediatric population and there is a comparable inhibition of IMPDH activity by MPA in children and adolescents after renal transplantation.
    Preview · Article · Jan 2012 · European Journal of Clinical Pharmacology
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    David Czock · Frieder Keller · Hanna M Seidling
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    ABSTRACT: AIM Drug dosage adjustments in renal impairment are usually based on estimated individual pharmacokinetics. The extent of pharmacokinetic changes in patients with renal impairment must be known for this estimation. If measured data are not available, an estimate based on drug elimination in urine of healthy subjects or patients with normal renal function is commonly made. This is not reliable, however, if renal drug metabolism is involved, as is presumably the case for many peptide and protein drugs. In the present study a new method to predict pharmacokinetic changes for such drugs based on molecular weight was derived. METHODS Articles reporting measured pharmacokinetics of peptide and protein drugs in patients with severe renal impairment or end-stage renal disease were identified from the scientific literature, the pharmacokinetic parameter values were extracted and a statistical data synthesis was performed. A sigmoid Emax model was applied and fitted to the data and the prediction error was analyzed. RESULTS Overall, 98 peptide and protein drugs were identified. Relevant pharmacokinetic data in patients with renal impairment were found for 21 of these drugs. The average drug clearance was 30% and the average prolongation in half-life was 3.1-fold for low molecular weight peptides or proteins. The median root squared percentage of the prediction error was 18% (drug clearance) and 12% (half-life). CONCLUSION An apparently continuous non-linear relationship between molecular weight and pharmacokinetic alterations in patients with severe renal impairment was found. The derived equations could be used as a rough guide for decisions on drug dosage adjustments in such patients.
    Preview · Article · Jan 2012 · British Journal of Clinical Pharmacology

Publication Stats

1k Citations
176.05 Total Impact Points


  • 2006-2015
    • Universität Heidelberg
      • • Department of Clinical Pharmacology and Pharmacoepidemiology
      • • University Hospital of Internal Medicine
      Heidelburg, Baden-Württemberg, Germany
  • 2009
    • evaplan at the University Hospital Heidelberg
      Heidelburg, Baden-Württemberg, Germany
  • 1998-2008
    • Universität Ulm
      • Department of Internal Medicine
      Ulm, Baden-Württemberg, Germany