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Abstract

F. Keller, U. Ludwig and D. Czock

Nephropharmacology is becoming a branch of its own within clinical pharmacology and in recent years has been the subject of several symposia. The background of these developments is interesting both clinically and pharmacokinetically. Indeed renal pharmacokinetics has been a driving force in clinical pharmacokinetics as a whole.

Kunin et al. [1959] were the first to demonstrate the dependence of drug elimination half-life (t1/2) on renal function. Luzius Dettli [1974] had the enlightening idea that the elimination rate constant (Ke) or the drug clearance (CL) could be linearly correlated to the renal function as measured by the creatinine clearance (CreaCL).

CL = CLnonren + A × CreaCL
A = (CLnorm – CLnonren)/CreaCLnorm

The most reliable estimate of the nonrenal clearance (CLnonren) corresponds to the drug clearance in patients with renal failure. By linear interpolation, drug dose can be adjusted to the individual renal function based on the specific pharmacokinetic parameters of each drug [Bennett et al. 1977]. Hallmark studies have demonstrated an improvement in survival after individually adjusting dosage according to renal function [Evans et al. 1998].

Pharmacokinetics is an essential requirement for individual dosage adjustment. However, it has to be used in combination with pharmacodynamics [Holford 1999] and the mathematical correlation between pharmacokinetic and pharmacodynamic parameters must be explicitly defined.

After repetitive administration with interval (t), the area under the effect time curve (AUETC) is a function of the specific kinetic (t1/2, Cpeak, Ctrough) and dynamic (H, CE50) parameters of the respective drug [Czock and Giehl 1995].

AUETCt = n (1.44 Emax t1/2/H)
ln[(CpeakH + CE50H)/(CtroughH + CE50H)]

Using such correlations the expert will be able to apply calculation algorithms in specialized computer systems [Proost and Punt 2003]. Such algorithms use parameters that can be retrieved from scientific publications and recorded in a structured database [Keller et al. 1998].
Looking to the future, the new subject of pharmacogenetics will need to be translated into pharmacokinetic and pharmacodynamic parameters before it can be applied to drug dose individualization. At the present time, of most practical interest for the nephropharmacologist are the fields of renal drug toxicity, toxicity prevention [Haeussler et al. 2004] and the specific drug therapy of renal disease.
During the next few months several articles, on aspects of this editorial, and which were presented at the 9th NephroPharmacology meeting in Ulm, Germany 2005, will be published in this journal.

References

Bennett WM, Singer I, Golper T, Feig P, Coggins CJ. Guidelines for drug therapy in renal failure. Ann Intern Med. 1977; 86: 754-783.
Czock D, Giehl M. Aminoglycoside pharmacokinetics and -dynamics: a nonlinear approach. Int J Clin Pharmacol Ther. 1995; 33: 537-539.
Dettli LC. Drug dosage in patients with renal disease. Clin Pharmacol Ther. 1974; 16: 274-280.
Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui CH. Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med. 1998; 338: 499-505.
Haeussler U, Riedel M, Keller F. Free reactive oxygen species and nephrotoxicity of contrast agents. Kidney Blood Press Res. 2004; 27: 167-171.
Holford NH. Target concentration intervention: beyond Y2K. Br J Clin Pharmacol. 1999; 48: 9-13.
Keller F, Frankewitsch T, Zellner D, Simon S, Czock D, Giehl M. Standardized structure and modular design of a pharmacokinetic database. Comput Methods Programs Biomed. 1998; 55: 107-115.
Kunin CM, Rees SB, Merrill JP, Finland M. Persistence of antibiotics in blood of patients with acute renal failure. I. Tetracycline and chlortetracycline. J Clin Invest. 1959; 38: 1487-1497.
Proost JH, Punt NC. Dose individualization in PharmDIS-e+. Int J Clin Pharmacol Ther. 2003; 41: 451-458.

Abstract

D. Czock

Medical Department, Division of Nephrology, University Hospital Ulm, Germany
Objective: The most commonly applied pharmacodynamic model is the sigmoid Emax model which can be applied for evaluation of dose adjustment schemes in renal failure. It is not known whether the Hill coefficient (H) is a shape factor that only improves the mathematical fit or whether the Hill coefficient is a pharmacodynamic parameter that independently affects drug effects and drug dosage adjustment. Methods: We performed simulations applying a mechanism-based mathematical pharmacokinetic-pharmacodynamic model for antimicrobial drugs. For the case of renal failure, two dose adjustment rules were evaluated. Results: Administering the drug as 3 dose fractions per day increased the predicted total effect in the case of H = 1 but decreased the predicted total effect in the case of H = 2 compared to once-daily dosing. In renal failure, administration of the normal dose and prolongation of the interval leads to an increased total effect for the simulated drugs for both cases, namely H = 1 and H = 2. However, reducing the dose in renal failure might produce underdosage for a drug with a high Hill coefficient. Conclusion: The predicted effects of once- versus thrice-daily dose fractions as well as the predicted effects of dose reduction versus interval prolongation in renal failure critically depend on the Hill coefficient. Methods to estimate the Hill coefficient more precisely should be explored.Correspondence to:
Dr. D. Czock
University Hospital Ulm
Medical Department, Division of Nephrology
Robert-Koch-Straße 8, 89081 Ulm, Germany
Email: [email protected]

Abstract

D. Czock, U. Aisenpreis, F.M. Rasche and P.M. Jehle and P.M. Jehle

¹Nephrology Division, University Hospital, Ulm, and ²Hospital for Internal Medicine, Hospital of the Paul-Gerhardt-Stiftung, Lutherstadt Wittenberg, Germany
Objective: Lispro-insulin, after subcutaneous injection in patients with normal renal function, is absorbed faster and has a faster onset of action when compared to regular insulin. However, the pharmacokinetics and pharmacodynamics of lispro-insulin in renal failure have not yet been investigated. Patients and methods: Eight patients with diabetes mellitus on long-term hemodialysis received an individualized dose of regular insulin or lispro-insulin in a crossover design. Blood glucose and insulin concentrations were measured before and after the subcutaneous insulin injections. Results: Plasma insulin concentrations increased faster (time of maximum concentration t_max 20 vs 40 minutes, p = 0.01) and were higher (standardized maximum concentration C_max/ D 13.6 vs 6.1 mU/ml/U, p = 0.01) after lispro-insulin compared to regular insulin. The area under the curve, clearance and parameters of the hypoglycemic action for the 2 insulin products did not differ significantly, but there was a trend to minimum blood glucose level (time of the blood glucose minimum, Gt_min) to occur earlier with lispro-insulin (120 vs 210 minutes, p > 0.05). Differences in elimination half-life and volume of distribution were explained by flip-flop pharmacokinetics in the case of regular insulin. Conclusions: In hemodialysis patients with diabetes mellitus, lispro-insulin is absorbed faster than regular insulin. Differences in the effects of lispro- and regular insulin can be explained by the differences in pharmacokinetics.

Abstract

L. Renders¹, D. Czock², H. Schöcklmann¹ and U. Kunzendorf¹

¹Division of Nephrology, University Hospital Schleswig-Holstein, Campus Kiel, and ²Division of Nephrology, University Hospital Ulm, Germany
Objective: Therapy of elevated cholesterol serum concentrations is often necessary in patients with kidney transplants. However, the pharmacokinetics of HMG-CoA reductase inhibitors when administered in combination with sirolimus and cyclosporin A (CsA) have not been determined. The aim of this study was to investigate the pharmacokinetics of cerivastatin when administered in combination with sirolimus in patients with kidney transplants, and to review the literature with regard to the differences in pharmacological behavior between sirolimus, CsA and tacrolimus. Methods: Patients (n = 7) with a stable and functioning kidney transplant and elevated LDL cholesterol serum concentrations were included in the study. After an observation period of 3 months, and whilst receiving sirolimus and CsA, cerivastatin (0.2 mg daily) was administered for a period of 3 months. Pharmacokinetic parameters were calculated on Day 1 and 3 months after initiation of cerivastatin therapy. Routine laboratory parameters and clinical adverse events were monitored throughout the study period. Results: Single-dose cerivastatin AUC was 2 to 3-fold higher in comparison to published values obtained in healthy subjects. The accumulation ratio of cerivastatin (after 3 months/ Day 1) was 1.6. Sirolimus and CsA trough levels, and the sirolimus AUC did not differ after single dose and multiple doses of cerivastatin. Conclusions: The combination therapy of cerivastatin with sirolimus and CsA leads to a significant increase in cerivastatin exposure. Additional drug monitoring of sirolimus and CsA is not necessary.

Abstract

Nieren- und Hochdruckkrankheiten, Jahrgang 35, Nr. 12/2006, S. 533–537

Pharmakodynamische Dosisanpassung von Medikamenten bei Nieren-insuffizienz: Bedeutung des Hill-Koeffizienten

D. Czock

Correspondence to:
Dr. med. D. Czock
Sektion Nephrologie
Klinik für Innere Medizin I
Zentrum für Innere Medizin
Universitätsklinikum Ulm
Robert-Koch-Straße 8
D–89081 Ulm

Email: [email protected]

Abstract

Nieren- und Hochdruckkrankheiten, Jahrgang 32, Nr. 2/2003, S. 74-80

Vorschläge zur Dosisanpassung bei Niereninsuffizienz

D. Czock, B. Bösler, F.M. Rasche, R. Lukas und F. Keller

Abstract

F.M. Rasche, F. Keller, G. Kunze, B. Boesler and D. Czock

Medical Department, Division of Nephrology, University Hospital Ulm, Germany
Aims: Single daily dose cyclosporine (SDD-CsA) might be a new option providing comparable efficacy, increased compliance and less nephrotoxicity compared to standard twice-daily dose cyclosporine (TDD-CsA). The aim of this trial was to prove the feasibility of SDD-CsA as primary and secondary maintenance therapy in patients with nephrotic syndrome. Methods: We treated 25 adult patients with nephrotic syndrome and chronic primary glomerulonephropathy with SDD-CsA for a period of 12 months or more. 12 patients were pre-treated with twice-daily dose cyclosporine (TDD-CsA) and were then switched secondarily to a single daily dose after a median period of 8 months (sSDD-CsA). 13 patients were treated primarily with single daily dose cyclosporine (pSDD-CsA). Results: In primary SDD-CsA patients, proteinuria decreased significantly from 9.2 – 0.8 g/l (p = 0.02) and serum protein increased significantly from 54 – 71 g/l (p = 0.03) during the study period. In secondary SDD-CsA patients, serum protein increased further (64 – 69, p = 0.04) after switching to SDD-CsA. In secondary SDD-CsA patients, the median total daily CsA dose was significantly lower (200 mg) with SDD-CsA compared to previous twice-daily dosing (300 mg, p = 0.01). Serum creatinine did not differ significantly before and after therapy and between the groups. Conclusions: SDD-CsA is effective in patients with nephrotic syndrome as primary and secondary maintenance therapy. SDD-CsA allows for significantly lower total daily doses, probably with less nephrotoxicity.Correspondence to:
Prof. F. Keller University Hospital Ulm Medical Department Division of Nephrology Robert-Koch-Straße 8 89081 Ulm, Germany
Email: [email protected]

Abstract

D. Czock¹, F. Keller², W.D. Paar³ und F. Thalhammer⁴

¹Abteilung Innere Medizin VI, Klinische Pharmakologie und Pharmakoepidemiologie, Universität Heidelberg, ²Abteilung Innere Medizin I, Sektion Nephrologie, Universitätsklinikum Ulm, ³Medizinische Abteilung, Sanofi-Aventis Deutschland GmbH, Berlin, ⁴Klinische Abteilung für Infektionen und Tropenmedizin, Universitätsklinik für Innere Medizin I, Medizinische Universität Wien
Bei kritisch kranken Patienten mit Nierenversagen ist die Pharmakokinetik vieler Arzneimittel sowohl krankheitsbedingt als auch durch die Nierenersatztherapie verändert. Die Basis für eine adäquate Dosisanpassung ist die möglichst akkurate Schätzung der individuellen Pharmakokinetik. Die Grundlage für die Auswahl der Dosierungsregel sollte die Pharmakodynamik der Substanz sein. Im vorliegenden Artikel stellen wir eine neue Methode zur Herleitung von Pharmakokinetik-Parametern während kontinuierlicher Nierenersatztherapie vor, welche auf einer Interpolation von publizierten Parameterwerten beruht, und wenden diese bei 26 ausgewählten Antibiotika an. Aus den berechneten Arzneimittelspiegeln ergab sich, dass unter laufender Hämofiltration mit einem Ultrafiltratfluss von 2 l/h die Akkumulation der ausgewählten Antibiotika gemessen an den Spitzenspiegeln moderat ist. Eine Dosisanpassung mit der erweiterten Kunin-Regel erscheint bei schweren Infektionen adäquat. Bei schwersten Infektionen lässt sich für viele Antibiotika unter laufender Hämofiltration sogar eine unveränderte Dosierung rechtfertigen.Correspondence to:
PD Dr. med. D. Czock; Abteilung Innere Medizin VI, Klinische Pharmakologie und Pharmakoepidemiologie, Medizinische Klinik (Krehl-Klinik), Universität Heidelberg, Im Neuenheimer Feld 410, D–69120 Heidelberg
Email: [email protected]

Abstract

F. Keller¹, M. Giehl², D. Czock¹ and D. Zellner¹

¹Nephrology, University Ulm, and ²Department of Radiology, University Hospital Benjamin Franklin, Berlin
Non-linear phenomena are observed with enzyme kinetics, protein binding, pharmacokinetics or pharmacodynamics. The Hill equation, the Michaelis-Menten equation extended by a power coefficient, is traditionally used for sigmoid curve fitting. Sigmoid saturation phenomena can also be described by exponential functions (1-exp), extended by a power coefficient such as those derived by Hodgkin, Douglas or Gompertz. Comparing the 4 equations, the sigmoid 1-exp function in the form of Hodgkin and Huxley comes closest to the principle of simplicity and succinctness with regard to definition, slope and flexibility of the inflection point. To compare the applicability, a standardized sample of 250 curves was generated by each 1 of the 4 equations and mutually fitted with the remaining 3. The Hill equation gives the closest fit with the data generated by the other functions. The Douglas variant exhibits the highest rate of convergence. The Gompertz function provides the basic feature of a baseline effect. Conclusion: The sigmoid functions investigated (Hill, Hodgkin, Douglas, Gompertz) have differing characteristics and can be used interchangeably for solving specific problems in non-linear modeling.Correspondence to:
Dr. F. Keller; Nephrology, University Hospital, Robert-Koch-Straße 8, D-89070 Ulm, Germany
Email: [email protected]

Abstract

F. Keller¹, M. Giehl², D. Czock¹ and D. Zellner¹

¹Nephrology, University Ulm, and ²Department of Radiology, University Hospital Benjamin Franklin, Berlin
Non-linear phenomena are observed with enzyme kinetics, protein binding, pharmacokinetics or pharmacodynamics. The Hill equation, the Michaelis-Menten equation extended by a power coefficient, is traditionally used for sigmoid curve fitting. Sigmoid saturation phenomena can also be described by exponential functions (1-exp), extended by a power coefficient such as those derived by Hodgkin, Douglas or Gompertz. Comparing the 4 equations, the sigmoid 1-exp function in the form of Hodgkin and Huxley comes closest to the principle of simplicity and succinctness with regard to definition, slope and flexibility of the inflection point. To compare the applicability, a standardized sample of 250 curves was generated by each 1 of the 4 equations and mutually fitted with the remaining 3. The Hill equation gives the closest fit with the data generated by the other functions. The Douglas variant exhibits the highest rate of convergence. The Gompertz function provides the basic feature of a baseline effect. Conclusion: The sigmoid functions investigated (Hill, Hodgkin, Douglas, Gompertz) have differing characteristics and can be used interchangeably for solving specific problems in non-linear modeling.Correspondence to:
Dr. F. Keller; Nephrology, University Hospital, Robert-Koch-Straße 8, D-89070 Ulm, Germany
Email: [email protected]

Abstract

Intensiv- und Notfallbehandlung, Jahrgang 27, Nr. 4/2002, S. 172-183

SIRS und Sepsis – akutes Nierenversagen – Nierenersatzverfahren und Dosisanpassung von Medikamenten

D. Czock und F. Keller

Sektion Nephrologie, Abteilung Innere Medizin II, Universitätsklinikum Ulm
Die Nierenfunktion kann durch ein “Systemisches
Inflammatorisches Response
Syndrom” (SIRS) oder eine Sepsis deutlich
beeinträchtigt werden. Bei etwa 2/3 aller Medikamente
muß man dann die Dosierung anpassen.
Diese Dosisanpassung ergibt sich aus
der geänderten Pharmakokinetik, abhängig
von der Nierenfunktion. Eine Extrapolation,
ausgehend von der renal eliminierten Fraktion
unter Normalbedingungen, ist oft unzureichend,
weil diese den renalen Metabolismus
unterschätzt. Medikamente, die von der Niere
eliminiert werden, sind wasserlöslich. Deshalb
wird durch die Hämodialyse oft ein relevanter
Anteil entfernt. In diesem Fall muß
eine zusätzliche Supplementärdosis nach der
Hämodialyse gegeben werden. Bei kontinuierlicher
Hämofiltration muß wegen der extrakorporalen
Arzneimittelclearance eine höhere
Dosis verwendet werden als bei anurischen
Patienten. Für Patienten auf der Intensivstation
ist oft die antimikrobielle Therapie
von entscheidender Bedeutung. Dort ist eine
Dosisanpassung nach der Halbierungsregel
von Kunin wirkungssicherer als nach der Proportionalitätsregel
von Dettli, da nur bei ersterer
sicher wirksame Spitzenspiegel erreicht
werden. In Zukunft wird eine Dosisanpassung
nach pharmakodynamischen Parametern
eine zunehmende Rolle spielen. Ziel
ist, jeden Patienten individuell zu behandelnCorrespondence to:
Prof. Dr. med. F. Keller
Sektion Nephrologie
Abteilung Innere Medizin II
Universitätsklinikum Ulm
Robert-Koch-Straße 8
D-89070 Ulm

Abstract

Nieren- und Hochdruckkrankheiten, Jahrgang 31, Nr. 6/2002, S. 258-267

Medikamente in der Schwangerschaft: Ein tabellarischer Annex

D. Czock¹, F. Keller¹, F.M. Rasche¹, A. Schwarz² und C. Schimitzek³

¹Sektion Nephrologie, Medizinische Klinik, Universität Ulm, ²Nephrologie,
Medizinische Hochschule Hannover, ³Universitätsfrauenklinik Ulm
Correspondence to:
Dr. med. D. Czock
Sektion Nephrologie
Medizinische Klinik
Universität Ulm
Robert-Koch-Straße 8
D-89081 Ulm

Abstract

Nieren- und Hochdruckkrankheiten, Jahrgang 49, Nr. 9/2020, S. 395-400

Arzneimittel-Wechselwirkungen mit Immunsuppressiva

D. Czock¹ und C. Morath²

¹Abteilung Klinische Pharmakologie und Pharmakoepidemiologie, ²Nierenzentrum Heidelberg, Medizinische Klinik, Universitätsklinikum Heidelberg, Heidelberg
Erkennung und Berücksichtigung von potenziellen Arzneimittel-Wechselwirkungen sind bei Patienten, die mit Immunsuppressiva behandelt werden, besonders wichtig, da ansonsten im Einzelfall schwerwiegende Auswirkungen resultieren können. Wechselwirkungen beinhalten verstärkte Nebenwirkungen bei überlappender Toxizität, Auswirkungen von Arzneimitteln in der Komedikation, die zu einem deutlichen Anstieg oder zu einem Abfall der Konzentrationen eines Immunsuppressivum führen, sowie Auswirkungen von Immunsuppressiva auf Arzneimittel in der Komedikation.Correspondence to:
Prof. (apl) Dr. med. David Czock
Universitätsklinikum Heidelberg
Medizinische Klinik
Abteilung Klinische Pharmakologie und Pharmakoepidemiologie
Im Neuenheimer Feld 410
69120 Heidelberg
Email: [email protected]

Abstract

Nieren- und Hochdruckkrankheiten, Jahrgang 53, Nr. 4/2024, S. 213-215

Happy Birthday, lieber Prof. Keller!

S. Stracke und D. Czock

Abstract

Nieren- und Hochdruckkrankheiten, Jahrgang 55, Nr. 4/2026, S. 192-196

Scheinbare Nierenfunktionsverschlechterung durch Hemmung der renalen Kreatinin-Sekretion

D. Czock¹, K. Ebinger¹ und C. Sommerer²

¹Innere Medizin IX, Abteilung für Klinische Pharmakologie und Pharmakoepidemiologie, Medizinische Fakultät Heidelberg/Universitätsklinikum Heidelberg, Heidelberg, ²Innere Medizin X, Klinik für Nephrologie, Medizinische Fakultät Heidelberg/Universitätsklinikum Heidelberg, Heidelberg
Kreatinin wird hauptsächlich glomerulär filtriert, aber in einem gewissen Umfang auch tubulär sezerniert. Arzneimittel, die die tubuläre Kreatinin-Sekretion hemmen, können zu einem Anstieg des Kreatinin-Werts und einer Abnahme der geschätzten GFR führen, obwohl die tatsächliche GFR unverändert ist. Patient/-innen sollten vor Anwendung eines solchen Arzneimittels über diesen harmlosen Effekt informiert werden. Eine kurzfristige Kreatinin-Kontrolle hilft eine zufälligerweise zeitgleich auftretende akute Nierenschädigung auszuschließen und liefert einen Ausgangswert zur Beurteilung von zukünftigen Kreatinin-Messungen. Cystatin C ist von diesem Effekt nicht betroffen und kann bei der Beurteilung ebenfalls hilfreich sein.Correspondence to:
Prof. Dr. med. David Czock
Universität Heidelberg
Medizinische Fakultät Heidelberg/Universitätsklinikum Heidelberg
Innere Medizin IX
Abteilung für Klinische Pharmakologie und Pharmakoepidemiologie
Im Neuenheimer Feld 410
69120 Heidelberg
Email: [email protected]

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