Influence of Renal Function Estimation on Pharmacokinetic Modeling of Vancomycin in Elderly Patients

Abstract

Vancomycin is a renally excreted drug, and its body clearance correlates with creatinine clearance. However, the renal function estimation equation that best predicts vancomycin clearance has not been established yet. The objective of this study was to compare the abilities of different renal function estimation equations to describe vancomycin pharmacokinetics in elderly patients. The NPAG algorithm was used to perform population pharmacokinetic analysis of vancomycin concentrations in 78 elderly patients. Six pharmacokinetic models of vancomycin clearance were built, based on the following equations: CockcroftGault (CG), Jelliffe (JEL), Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) (both in milliliters per minute per 1.73 m 2 ), and modified MDRD and CKD-EPI equations (both in milliliters per minute). Goodness-of-fit and predictive performances of the six PK models were compared in a learning set (58 subjects) and a validation set (20 patients). Final analysis was performed to estimate population parameters in the entire population. In the learning step, the MDRD-based model best described the data, but the CG-and JEL-based models were the least biased. The mean weighted errors of prediction were significantly different between the six models (P ‫؍‬ 0.0071). In the validation group, predictive performances were not significantly different. However, the use of a renal function estimation equation different from that used in the model building could significantly alter predictive performance. The final analysis showed important differences in parameter distributions and AUC estimation across the six models. This study shows that methods used to estimate renal function should not be considered interchangeable for pharmacokinetic modeling and model-based estimation of vancomycin concentrations in elderly patients.

Implications of using the MDRD or CKD‐EPI equation instead of the Cockcroft–Gault equation for estimating renal function and drug dosage adjustment in elderly patients

“…Our group has investigated this question in elderly patients for two antimicrobials, gentamicin, and vancomycin, using a population pharmacokinetic approach. For gentamicin, the CG equation better predicted the drug clearance than the MDRD equation , while for vancomycin, the results were comparable except for CKD‐EPI which performed worst . These results and others suggest that a good marker of the GFR is not necessarily a good marker of drug clearance.…”

A new population pharmacokinetic model for vancomycin in patients with variable renal function: Therapeutic drug monitoring based on extended covariate model using CKD‐EPI estimation

“…SCRs <0.5 mg/dL were set to 0.5 mg/dL to avoid potential bias from an overestimation of renal function and to provide better estimates of vancomycin clearance in patients with low creatinine production . The MDRD and CKD‐EPI equations were adjusted to individual BSA values (GFR = (MDRD or CKD‐EPI) × (BSA/1.73)) to reduce the bias for population prediction . Number of patients with unstable renal function was determined when the eGFR, estimated using the CKD‐EPI equation, decreased by 30 mL/min from the previous or baseline eGFR data.…”

“…The use of a renal function estimation equation different from that used in model building could significantly alter the predictive performance for vancomycin PK . The performance of the same population PK model should be compared across various renal function estimation methods to consider the interchangeability of renal function estimation methods in population PK modelling.…”

Intravenous Vancomycin Dosing in the Elderly: A Focus on Clinical Issues and Practical Application

“…Conversely, a study by Tsuji et al found that if the serum creatinine is measured using the Jaffe method, instead of the IDMS method, then a correction of serum creatinine to 0.68 mg/dL is unnecessary within the CG equation [56]. Additionally, a study by Glatard et al found that the CG equation, MDRD equation, and CKD-EPI equations are not interchangeable when calculating vancomycin dosing and prediction of concentrations based on renal function [57]. The authors concluded that whichever equation clinicians utilize to calculate renal function should be the same equation used to dose renally eliminated drugs.…”

“…As vancomycin is approximately 90% renally eliminated unchanged in the urine [56, 57], it is imperative to accurately estimate renal function when calculating dosing regimens to help optimize the pharmacokinetic and pharmacodynamic properties of the drug. Cutler et al compared vancomycin kinetics in younger patients (mean age: 23 years) versus older patients (mean age: 68 years) [58].…”