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

Drug Dosing Considerations for Patients With CKD

Despite numerous published guidelines[46–51] regarding drug dosing for patients with reduced kidney function, there is insufficient evidence to guide decisions on many commonly used drugs. Indeed, occasionally recommendations derived from postmarketing studies are in conflict with the information in the official FDA or EMA product labeling and in recommendations found in frequently utilized reference sources. Before 1998, there were no official guidances regarding the explicit criteria for characterization of the relationship between drug PK and PD and kidney function. The FDA industry guidance issued in May 1998,[52] and the EMA guidance of 2004,[53] provided frameworks to help companies decide when they should conduct such a study and proposed explicit recommendations for study design, data analysis, and interpretation of the study results in product labeling.

PK and PD Data

The primary literature is replete with studies of the effect of CKD on the PK or PD of many of the most commonly prescribed medications. There are however many challenges associated with the application of these data in clinical practice. The volume of distribution (VD) of many drugs is increased in patients with moderate to severe CKD as well as in those with preexisting CKD who develop AKI.[2,54,55] This increase in V D may be the result of decreased protein binding, increased tissue binding, or alterations in body composition (for example, fluid overload). There is now good preclinical and emerging clinical evidence that CKD may lead to alterations in nonrenal clearance of many medications as the result of alterations in the activities of uptake and efflux transporters as well as cytochrome P450 (CYP enzymes) in the liver and other organs.[56–58] Prediction of the effect of impaired kidney function on the metabolism of a particular drug is however difficult and there is currently no quantitative strategy to predict changes for one drug based on data from another in the same class.

Patients with CKD may experience accumulation of metabolite(s) as well as the parent compound. This may result in unforeseen consequences as the metabolites of some drugs have significant pharmacologic activity. However, the PK and PD of metabolites are not often fully elucidated during clinical trials. Thus, the patient with CKD is being exposed to a new pharmacologic entity as the sum of the serum concentrations of the metabolite(s) and the parent compound are markedly different than those reported in patients with normal renal function.

The metabolite may have pharmacologic activity similar to that of the parent drug and thus contribute significantly to clinical response. Alternatively, the metabolite may have qualitatively dissimilar pharmacologic action; for example, normeperidine has central nervous system stimulatory activity that has caused seizures in some with CKD and AKI.[59] Because of the multiplicity of potential interactions of compounds that are primarily metabolized, the practical consequences of metabolite accumulation are difficult to predict.

Goals of Therapy

The desired dosage regimen adjustment goals for some agents are drug class specific. The desired goal may be: the maintenance of a similar peak, trough, or average steady-state drug concentration or for antibiotics an optimized PD measure such as the time above the minimum inhibitory concentration or the ratio of the drug area under the concentration time curve (AUC) to the minimum inhibitory concentration.[60] When there is a significant relationship between drug concentration and clinical response[61] (for example, aminoglycosides) or toxicity[62] (for example, phenytoin), then attainment of the specific target values becomes critical. If, however, no specific PK or PD target values have been reported, then a regimen goal of attaining similar average steady-state concentrations may be appropriate.

Drug Dosage Regimen Individualization

Most dosage adjustment guidelines have proposed the use of a fixed dose or interval for patients with broad ranges of kidney function that are different from those that are the foundation of the current CKD classification system.[54,55,63–65] Indeed, in the FDA guidance, normal kidney function has often been ascribed to anyone who has a CLcr >80–90 ml/min. In addition, mild, moderate, and severe impairments in kidney function are often defined differently among the PK studies, and each of these categories often encompasses a broad range of kidney function. The drug dosage adjustment recommendations that use broad ranges of kidney function may not be optimal for all patients whose kidney function lies within the range especially for agents that have a narrow therapeutic index.

Developing drug dosage adjustment recommendations for the CKD patient is often predicated on the attainment of the desired exposure goal (see above) at steady state that will surely be delayed because of the reduced clearance and prolonged half-life of the drug. In order to achieve the desired goal in a timely fashion, a stepwise approach that includes multiple considerations (see Table 3) for each individual drug has been proposed.[49] Indeed, in some patients, the clinical circumstance may suggest that a lower or higher dose be used than is indicated by the drug dosing guidelines. The following parameters may help guide individual therapy.

Loading Dose Most published guidelines do not recommend a loading dose, despite the well-documented evidence of altered V D of several drugs in CKD patients. Loading doses may be required if a drug has a long half-life and there is a need to rapidly achieve the desired steady-state concentrations. Furthermore, if the V D of a drug is significantly increased in CKD patients, a loading dose will likely be needed even if one was not routinely recommended for those with normal renal function. If the relationship between V D and CLcr has been characterized, then the V D should be estimated from that relationship. If that is not the case, a modified loading dose can be calculated if one knows the degree of change in the V D.

Maintenance Dose The predicted VD may be used with the predicted elimination rate constant (k) or total body clearance (CLT) of the drug to yield an adjusted dosing interval and maintenance dose when one desires to achieve a specific target serum concentration.[5,6,58] If the goal of a maintenance dosing regimen is however to attain a similar steady-state drug concentration time profile, that is, AUC, as would occur if the patient had normal kidney function, a simple proportional approach can be utilized. In general, prolonging the dosing interval but maintaining the same dose will result in the achievement of similar peak and trough concentrations as well as AUC and thus may be preferred.

Measurement of Therapeutic Drug Levels Measuring drug concentrations is one way to optimize therapeutic regimens and account for changes between and within individuals. Therapeutic drug monitoring requires availability of rapid, specific, and reliable assays and known correlations of drug concentration to therapeutic and adverse outcomes. In addition, hypoalbuminemia may influence interpretation of drug concentrations as the total drug concentration may be reduced even when the active unbound drug concentration is not. Unbound drug concentrations are often not clinically available, and therefore clinicians must empirically consider the impact of hypoalbuminemia in their interpretation of measured total drug concentrations (Table 4).[55,66,67]

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