Abstract

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

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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.
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• F. Keller
• U. Ludwig
• D. Czock

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