Drug Dosing Consideration in Patients With Acute and Chronic Kidney Disease

A Clinical Update From Kidney Disease: Improving Global Outcomes (KDIGO)

Gary R Matzke; George R Aronoff; Arthur J Atkinson Jr; William M Bennett; Brian S Decker; Kai-Uwe Eckardt; Thomas Golper; Darren W Grabe; Bertram Kasiske; Frieder Keller; Jan T Kielstein; Ravindra Mehta; Bruce A Mueller; Deborah A Pasko; Franz Schaefer; Domenic A Sica; Lesley A Inker; Jason G Umans; Patrick Murray

Disclosures

Kidney Int. 2011;80(11):1122-1137. 

In This Article

The Controversy

The pharmacokinetic era that began in the 1960s provided many methods to quantify drug concentrations and tools to characterize the influence of multiple factors including kidney function on the disposition of drugs.[5,6] In subsequent years the pharmaceutical industry began to investigate the relationship of kidney function and the PK as well as the PD of the drugs they had in development. There was no regulatory agency guidance during the 1970s to early 1990s that provided a framework for when investigations should be conducted and with what degree of rigor. Thus, much of the information on the PK/PD of drugs in patients with renal insufficiency was the result of clinician-initiated postmarketing studies. These studies often employed small sample sizes and resulted in the publication of frequently inconsistent or in some cases even conflicting recommendations regarding the need for drug dosage regimen adjustment. Comprehensive evaluations of clinical PK and PD of drugs and the resultant drug dosage regimen adjustment recommendations for CKD patients has been the topic of hundreds of articles in the past two decades and has become a standard feature in almost all clinical pharmacology and therapeutics textbooks. This wealth of data and expert opinion has fueled controversy regarding almost every step in the process of drug therapy individualization. The critical questions range from: What patient assessment considerations should be factored into the decision-making process? What is the most accurate and reliable index of 'kidney function' for drug dosing? What are the determinates of the desired therapeutic end points that guide therapy, the significance of risk associated with the accumulation of excessive drug and/or metabolite concentrations, and the degree of impact of AKI or CKD on the PK or PD of a drug? How to make pharmaceutical company-derived drug PK and PD readily available to clinicians? What is the predictive performance of the various methodologies to calculate the desired dosage regimen? What are the essential criteria that need to be met to reliably quantify the influence of RRTs on a drug PK and PD, which mathematical methods should be used to individualize drug therapy for those receiving RRTs, and finally what educational efforts should be developed to enhance drug prescribing for patients with AKI and CKD?

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