David Czock

Universität Heidelberg, Heidelburg, Baden-Württemberg, Germany

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Publications (72)161.15 Total impact

  • 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.
    Expert Opinion on Drug Metabolism &amp Toxicology 12/2014; · 2.94 Impact Factor
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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.
    Liver Transplantation 06/2014; · 3.94 Impact Factor
  • 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.
    Deutsches Ärzteblatt International 02/2014; 111(9):139-47. · 3.54 Impact Factor
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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.
    International Journal of Medical Informatics 01/2014; · 2.06 Impact Factor
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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.
    European Journal of Drug Metabolism and Pharmacokinetics 12/2013; · 1.31 Impact Factor
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    ABSTRACT: AIM(S): Impaired 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 was analysed in 24 patients with mild to severe liver cirrhosis (n = 4, 10, and 10 with CP class A, B, and C, respectively) and 6 patients without liver disease. RESULTS: Both 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 l/h, MELD ≥ 15: CLu = 805 ± 474 l/h, controls: CLu = 5815 ± 2649 l/h, P < 0.01). CONCLUSION: The correlation with unbound midazolam clearance suggests that either score predicts the metabolic capacity of CYP3A, the most relevant drug metabolising enzyme subfamily in humans.
    British Journal of Clinical Pharmacology 06/2013; · 3.69 Impact Factor
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    ABSTRACT: AIMS: Metformin pharmacokinetics depends on 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 transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1) polymorphisms. METHODS: Twenty-four healthy volunteers received metformin 500 mg tid for 10 days and trimethoprim 200 mg bid from day 5 to 10. Effects of trimethoprim on steady-state metformin pharmacokinetics were analyzed. RESULTS: In the population as a whole trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54 l/h, renal metformin clearance from 31 to 21 l/h, and prolonged half-life from 2.7 to 3.6 h (all P<0.01). This resulted in an increase in C(max) by 38% and in AUC 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 106 ml/min (P<0.01) and an increase in plasma lactate from 0.94 to 1.2 mmol/l (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.
    British Journal of Clinical Pharmacology 01/2013; · 3.69 Impact Factor
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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.
    Therapeutic drug monitoring 08/2012; 34(5):554-60. · 2.43 Impact Factor
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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.
    European Journal of Clinical Pharmacology 01/2012; 68(6):913-22. · 2.74 Impact Factor
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    ABSTRACT: • Renal impairment may affect the pharmacokinetics of peptide and protein drugs. • Molecular size is a predictor. Small molecules are eliminated by the kidneys, whereas large molecules (>67 kDa) are not. • Urinary recovery of peptide and protein drugs in healthy volunteers is not predictive for pharmacokinetic changes in patients with renal impairment. • An apparently continuous non-linear relationship between molecular weight and pharmacokinetic alterations as observed in patients with severe renal impairment or end-stage renal disease is described. • Potentially relevant pharmacokinetic changes were found for drugs with a molecular weight below 50 kDa. • Analysis of observed pharmacokinetics in patients with severe renal impairment may be a useful approach, especially when urinary recovery in healthy volunteers is not predictive. 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. 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 E(max) model was applied and fitted to the data and the prediction error was analyzed. 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). 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.
    British Journal of Clinical Pharmacology 01/2012; 74(1):66-74. · 3.69 Impact Factor
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    ABSTRACT: The optimal balance between efficacy and toxicity of tacrolimus (Tac) treatment remains unsolved. The quantification of nuclear factor of activated T cell (NFAT)-regulated gene expression may provide a tool to monitor the individual susceptibility to Tac. Expression of NFAT-regulated genes (interleukin-2, interferon-gamma, and granulocyte-macrophage colony stimulating factor) in peripheral blood from renal transplant patients (N = 73) was measured by quantitative real-time polymerase chain reaction (at C0, C1.5, and C4) and correlated to clinical endpoints in a 1-year observation period. In a subgroup (n = 10), NFAT expression was quantified over a 12-hour dose interval. Median daily Tac dose of 73 stable renal transplant patients [median age 47 years (range 19-69 years)] was 5 mg (1-13), Tac trough (C0), 1.5-hour (C1.5) and 4-hour (C4) concentrations were 8.5 mcg/L (3-20), 20 mcg/L (4.7-50.4), and 14.5 mcg/L (4.5-37.5), respectively. The mean residual expression of all 3 NFAT-regulated genes was 21% at C1.5 (1-84) and 35% at C4 (2-88). The relative reduction of gene transcripts was inversely correlated with the individual Tac blood concentrations. Seven patients had cytomegalus virus viremia during the observation period, and their residual NFAT-regulated gene expression at C1.5 was significantly lower [13% (1-21) versus 26% (1-84), P = 0.02] compared with those without viremia despite comparable Tac blood concentrations (6.3 versus 8.6 mcg/L). Monitoring of NFAT-regulated gene expression in Tac-treated transplant recipients provides a tool to assess the individual response to Tac, identify patients at the risk of developing cytomegalus virus viremia, and may, thus, help to select the optimal Tac dose with respect to safety and toxicity.
    Therapeutic drug monitoring 08/2011; 33(4):373-9. · 2.43 Impact Factor
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    ABSTRACT: Very low voriconazole concentrations are commonly observed during therapeutic drug monitoring. Possible mechanisms include inappropriate dose selection, rapid metabolism (as a result of genetic polymorphisms or enzyme induction), and also nonadherence. We aimed to develop a method to distinguish between rapid metabolism of and nonadherence to voriconazole by quantification of voriconazole metabolites. In addition, the relevance of common genetic polymorphisms of CYP2C19 was assessed. In a retrospective study, samples with voriconazole concentrations 0.2 μg/mL or less in routine therapeutic drug monitoring (as quantified by high-performance liquid chromatography) were evaluated. Voriconazole and its N-oxide metabolite were quantified in residual blood using a highly sensitive liquid chromatography-tandem mass spectroscopy method (lower limit of quantitation = 0.03 μg/mL). Genetic polymorphisms of CYP2C19 were determined by real-time polymerase chain reaction using the hybridization probe format and the polymerase chain reaction-random fragment length polymorphism format. A total of 747 routine therapeutic drug monitoring plasma/blood samples of 335 patients treated with systemic voriconazole were analyzed and in 18.7% of all samples, voriconazole concentrations 0.2 μg/mL or less were found. In 32 samples (30 patients) with adequate dosage and timing of blood withdrawal, nonadherence was strongly suspected in seven patients because voriconazole-N-oxide concentrations were below 0.03 μg/mL, which was not observed in a reference group of 51 healthy volunteers with controlled drug intake. In 10 patients, of whom EDTA blood was available, the ultrarapid metabolizer genotype (CYP2C19*1\*17, CYP2C19*17\*17) was found in 80% and its prevalence was significantly higher as compared to a reference group (P = 0.02). In conclusion, quantification of voriconazole-N-oxide allowed for detection of suspected nonadherence in one of four patients with very low voriconazole concentrations. In the remaining patients, ultrarapid metabolism resulting from the CYP2C19*17 polymorphism appears to play a major role. Thus, in the case of voriconazole therapy failure, both nonadherence and genetic factors have to be considered.
    Therapeutic drug monitoring 02/2011; 33(1):86-93. · 2.43 Impact Factor
  • Deutsches Ärzteblatt International 02/2011; 108(7):114-5. · 3.54 Impact Factor
  • David Czock, Frieder Keller
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    ABSTRACT: Nephrotoxicity is a common and often clinically relevant adverse drug reaction. Mechanisms include vascular, tubulo-toxic, tubulo-obstructive, and immunological effects. Drug-drug interactions may occur at a pharmacokinetic or pharmacodynamic level. Such interactions can both increase (cisplatin and aminoglycoside) but also protect from nephrotoxicity (cidofovir and probenecid).Important measures for preventing nephrotoxicity are (1) consideration of potential pharmacokinetic and pharmacodynamic interactions when prescribing a drug, (2) prescription of nephrotoxic drugs for the shortest possible period, (3) detection of high-risk patients, and (4) consideration of hydration and prophylactic comedication.
    Therapeutische Umschau 01/2011; 68(1):11-8.
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    ABSTRACT: Roughly 20% of patients in hospital have impaired kidney function. This is frequently overlooked because of the creatinine-blind range in which early stages of renal failure are often hidden. Chronic kidney disease is divided into 5 stages (CKD 1 to 5). Selective literature search. Methotrexate, enoxaparin and metformin are examples of drugs that should no longer be prescribed if the glomerular filtration rate (GFR) is 60 mL/min or less. With antidiabetic (e.g. glibenclamide), cardiovascular (e.g. atenolol) or anticonvulsive (e.g. gabapentin) drugs, the advice is to use alternative preparations such as gliquidone, metoprolol or carbamazepine which are independent of kidney function. Drug dose adjustment should be considered with antimicrobial (e.g. ampicillin, cefazolin), antiviral (e.g. aciclovir, oseltamivir) and, most recently, also for half of all chemotherapeutic and cytotoxic drugs in patients with impaired kidney function (with e.g. cisplatin, for instance, but not with paclitaxel). Decisions concerning drug dose adjustment must be based on the pharmacokinetics but this is an adequate prerequisite only in conjunction with the pharmacodynamics. There are two different dose adjustment rules: proportional dose reduction according to Luzius Dettli, and the half dosage rule according to Calvin Kunin. The latter leads to higher trough concentrations but is probably more efficient for anti-infective therapy.
    Deutsches Ärzteblatt International 09/2010; 107(37):647-55; quiz 655-6. · 3.54 Impact Factor
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    ABSTRACT: Our intention was to assess knowledge and requirements related to drug dose adjustment in patients with impaired kidney function. In 2005, we sent a questionnaire containing 22 questions to nephrologists in Germany and Austria. With 77 responses, the study was not representative. However, it was probably of importance for the target group of practising physicians and potential users of a future drug information system. Only 28% of the responding colleagues use the package inserts; these are obviously not considered to be an obligatory guideline for dose adjustment. The most common dosing problems (p < 0.05) were associated with anti-infective (48%) and anti-cancer drugs (25%). The greatest problems with dosing were encountered within intensive care units (29%). The risk of excessive dosing is estimated significantly more serious than the risk of underdosing (51% vs. 23%, p = 0.02). There was support for the statement that for cephalosporin antibiotics the trough levels are more important than peak levels (58% vs. 27%, p < 0.01). However, only 8% knew that in patients with impaired kidney function, trough concentrations of aminoglycosides and vancomycin need to be higher than in patients with normal kidney function for adequate peak levels to be obtained. Forty-five percent of respondents erroneously presumed that ceftriaxone must be adjusted to the kidney function. Half of the respondents were incorrect in assuming that ceftriaxone or moxifloxacin would be removed by dialysis. We see the need for more knowledge-based information on drug dosing in patients with kidney impairment and those in the intensive care unit. The risk to life posed by underdosage might be underestimated, especially for anti-infective drugs.
    Wiener klinische Wochenschrift 08/2010; 122(15-16):479-85. · 0.81 Impact Factor
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    ABSTRACT: Sulfobutylether-beta-cyclodextrin (SBECD), a large cyclic oligosaccharide that is used to solubilize voriconazole (VRC) for intravenous administration, is eliminated mainly by renal excretion. The pharmacokinetics of SBECD and voriconazole in patients undergoing extracorporeal renal replacement therapies are not well defined. We performed a three-period randomized crossover study of 15 patients with end-stage renal failure during 6-hour treatment with Genius dialysis, standard hemodialysis, or hemodiafiltration using a high-flux polysulfone membrane. At the start of renal replacement therapy, the patients received a single 2-h infusion of voriconazole (4 mg per kg of body weight) solubilized with SBECD. SBECD, voriconazole, and voriconazole-N-oxide concentrations were quantified in plasma and dialysate samples by high-performance liquid chromatography (HPLC) and by HPLC coupled to tandem mass spectrometry (LC-MS-MS) and analyzed by noncompartmental methods. Nonparametric repeated-measures analysis of variance (ANOVA) was used to analyze differences between treatment phases. SBECD and voriconazole recoveries in dialysate samples were 67% and 10% of the administered doses. SBECD concentrations declined with a half-life ranging from 2.6 +/- 0.6 h (Genius dialysis) to 2.4 +/- 0.9 h (hemodialysis) and 2.0 +/- 0.6 h (hemodiafiltration) (P < 0.01 for Genius dialysis versus hemodiafiltration). Prediction of steady-state conditions indicated that even with daily hemodialysis, SBECD will still exceed SBECD exposure of patients with normal renal function by a factor of 6.2. SBECD was effectively eliminated during 6 h of renal replacement therapy by all methods, using high-flux polysulfone membranes, whereas elimination of voriconazole was quantitatively insignificant. The SBECD half-life during renal replacement therapy was nearly normalized, but the average SBECD exposure during repeated administration is expected to be still increased.
    Antimicrobial Agents and Chemotherapy 04/2010; 54(6):2596-602. · 4.57 Impact Factor
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    ABSTRACT: Drug-drug interactions can be used to enhance effectiveness but they are also a significant cause of adverse drug reactions. Alterations in liberation, absorption, distribution, metabolism, and excretion may all affect the pharmacokinetics of a drug. Cytochrome P450 enzymes and drug transporters like ABC-transporters determine the clearance of many drugs leading to alterations in therapeutic effect. In contrast pharmacodynamic drug interactions will alter drug effects in the absence of concentration changes of the co-administered drug. Alterations of a drug effect may require changes in dose to maintain the therapeutic effect.
    Der Internist 03/2010; 51(3):359-69; quiz 370. · 0.33 Impact Factor
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    ABSTRACT: In people who are aged >65 years, pharmacokinetics are influenced more by the loss of kidney function than by the aging process of any other organ. A GFR of 30 to 60 ml/min, suggestive of stage 3 kidney disease, is observed in 15 to 30% of elderly people. Drug dosing must be adjusted to both changing pharmacokinetics and pharmacodynamics; the pharmacodynamics might be influenced by the aging of other organs, too. Using our NEPharm database, we extracted abstracts with pharmacokinetic parameters since 1999 from a weekly PubMed search. The recorded data were analyzed and compared with published recommendations on drug dosage and use in the elderly. Purely age-related changes in pharmacokinetic parameters were recorded from publications on 127 drugs. The analysis of our NEPharm records revealed an average (mean +/- SD) age-related prolongation of half-life of 1.39-fold (corresponding to +39 +/- 61%). Contrasting to common opinion, mean changes in clearance (-1 +/- 54%) and volume of distribution (+24 +/- 56%) were even less. The modest changes in pharmacokinetics do not suggest general dosage modifications in the elderly for most drugs. Changes in pharmacodynamics justify the common medication rule in the elderly-"start low + go slow"-especially for drugs that act on the central nervous system; however, in the case of anti-infective and anticancer therapy, the rule should be "hit hard = start high + go fast" to produce the target effect also in the elderly.
    Clinical Journal of the American Society of Nephrology 02/2010; 5(2):314-27. · 5.07 Impact Factor
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    ABSTRACT: ZIELSETZUNG: Wir wollten den Kenntnisstand und Informationsbedarf von nephrologisch tätigen Ärzten zur Arzneimitteldosierung bei Niereninsuffizienz erfassen. METHODEN: Hierzu haben wir im Jahr 2005 unter den in Deutschland und Österreich registrierten Mitgliedern der Gesellschaft für Nephrologie einen Umfragebogen versandt. Es wurden uns 77 Bögen zurückgeschickt. Die Untersuchung war zwar nicht repräsentativ, die Antworten zu insgesamt 22 Fragen sind aber aufschlussreich. ERGEBNISSE: Zur Dosisanpassung benutzen nur 28 % der Antwortenden die Fachinformation, die somit nicht als bindend eingeschätzt wird. Am signifikant häufigsten (p < 0.05) treten Dosierungsprobleme bei Antiinfektiva (48 %) und Zytostatika (25 %) auf. Die größten Dosierungsprobleme werden auf Intensivstation gesehen (29 %). Die Überdosierung wird signifikant (p = 0.02) mehr gefürchtet als die Unterdosierung (51 % vs. 23 %). Zutreffend wurde angegeben (58 % vs. 27 %), dass bei Cefalosporinen die Talspiegel wichtiger sind als die Spitzenspiegel (p < 0.01). Aber nur 8 % wissen dass die Talspiegel von Aminoglykosiden oder Vancomycin bei Niereninsuffizienz höher liegen müssen als normal damit ausreichende Spitzenspiegel erreicht werden. Irrtümlich gehen 45 % der Antwortenden beim Ceftriaxon davon aus, dass eine Dosisanpassung an die Nierenfunktion nötig sei. Zu Unrecht hält knapp die Hälfte Ceftriaxon und Moxifloxacin für dialysierbar. SCHLUSSFOLGERUNG: Wir sehen einen deutlichen Informationsbedarf zu Fragen der Arzneimitteldosierung bei Patienten mit Niereninsuffizienz und auf Intensivstation. Die vitale Gefahr der subtherapeutischen Unterdosierung von Antiinfektiva wird wahrscheinlich unterschätzt. OBJECTIVE: Our intention was to assess knowledge and requirements related to drug dose adjustment in patients with impaired kidney function. METHOD: In 2005, we sent a questionnaire containing 22 questions to nephrologists in Germany and Austria. With 77 responses, the study was not representative. However, it was probably of importance for the target group of practising physicians and potential users of a future drug information system. RESULTS: Only 28% of the responding colleagues use the package inserts; these are obviously not considered to be an obligatory guideline for dose adjustment. The most common dosing problems (p < 0.05) were associated with anti-infective (48%) and anti-cancer drugs (25%). The greatest problems with dosing were encountered within intensive care units (29%). The risk of excessive dosing is estimated significantly more serious than the risk of underdosing (51% vs. 23%, p = 0.02). There was support for the statement that for cephalosporin antibiotics the trough levels are more important than peak levels (58% vs. 27%, p < 0.01). However, only 8% knew that in patients with impaired kidney function, trough concentrations of aminoglycosides and vancomycin need to be higher than in patients with normal kidney function for adequate peak levels to be obtained. Forty-five percent of respondents erroneously presumed that ceftriaxone must be adjusted to the kidney function. Half of the respondents were incorrect in assuming that ceftriaxone or moxifloxacin would be removed by dialysis. CONCLUSIONS: We see the need for more knowledge-based information on drug dosing in patients with kidney impairment and those in the intensive care unit. The risk to life posed by underdosage might be underestimated, especially for anti-infective drugs. SchlüsselwörterPharmakokinetik-Pharmakodynamik-Antiinfektiva-Dosisanpassung-Dettli-Kunin-Fragebogen-Nephrologen-NEPharm Datenbasis KeywordsPharmacokinetics-Pharmacodynamics-Anti-infectives-Dose adjustment-Dettli-Kunin-Questionnaire-Nephrologists-NEPharm database
    Wiener klinische Wochenschrift 01/2010; 122(15):479-485. · 0.81 Impact Factor

Publication Stats

648 Citations
161.15 Total Impact Points

Institutions

  • 2006–2014
    • Universität Heidelberg
      • Department of Clinical Pharmacology and Pharmacoepidemiology
      Heidelburg, Baden-Württemberg, Germany
  • 2010
    • University of Greifswald
      • Center for Internal Medicine
      Greifswald, Mecklenburg-Vorpommern, Germany
  • 1998–2009
    • Universität Ulm
      • • Faculty of Medicine
      • • Department of Internal Medicine
      Ulm, Baden-Wuerttemberg, Germany
  • 1995
    • Freie Universität Berlin
      Berlín, Berlin, Germany