Optimizing Vancomycin Dosing in Chronic Kidney Disease by Deriving and Implementing a Web-Based Tool Using a Population Pharmacokinetics Analysis

Abstract

Background: Chronic kidney disease (CKD) patients requiring intravenous vancomycin bear considerable risks of adverse outcomes both from the infection and vancomycin therapy itself, necessitating especially precise dosing to avoid sub- and supratherapeutic vancomycin exposure. Methods: In this retrospective study, we performed a population pharmacokinetic analysis to construct a vancomycin dose prediction model for CKD patients who do not require renal replacement therapy. The model was externally validated on an independent cohort of patients to assess its prediction accuracy. The pharmacokinetic parameter estimates and the equations were productized into a Web application (VancApp) subsequently implemented in routine care. The association between VancApp-based dosing and time-to-target concentration attainment, 30-day mortality, and nephrotoxicity were assessed postimplementation. Results: The model constructed from an initial cohort (n = 80) revealed a population clearance and volume of distribution of 1.30 L/h and 1.23 L/kg, respectively. External model validation (n = 112) demonstrated a mean absolute prediction error of 1.25 mg/L. Following 4 months of clinical implementation of VancApp as an optional alternative to usual care [VancApp (n = 22) vs. usual care (n = 21)], patients who had received VancApp-based dosing took a shorter time to reach target concentrations (median: 66 vs. 102 h, p = 0.187) and had fewer 30-day mortalities (14% vs. 24%, p = 0.457) compared to usual care. While statistical significance was not achieved, the clinical significance of these findings appear promising. Conclusion: Clinical implementation of a population pharmacokinetic model for vancomycin in CKD can potentially improve dosing precision in CKD and could serve as a practical means to improve vital clinical outcomes.

The Benefit of Individualized Vancomycin Dosing Via Pharmacokinetic Tools: A Systematic Review and Meta-analysis

“…26 Truong et al 39 showed that time to goal trough attainment for the PK and traditional groups was 54.0 ± 35.4 hours and 74.4 ± 45.7 hours, respectively ( P = 0.04). In contrast, Brinkman et al 25 and Dorajoo et al 37 did not find significant difference in time to target trough concentration between the 2 groups. Loading dose was included in the individualization regimen in studies conducted by Cardile et al 26 and Brinkman et al 25…”

“…All the 21 studies included were published in English, of which 3 were RCTs 22-24 and 18 were cohort studies. 13,16,17,25-39 These trials included 4346 patients in all. A total of 14 studies were conducted among adults 13,16,17,22,24-26,30,32,35-39 ; 1 study was conducted in pediatrics 33 and 1 included both adults and pediatric patients, 34 whereas the remaining were in neonates.…”

“…22 Concerning the specific mode in individualized dosing, 6 of which focused on the initial dosage design via estimated PK parameters, 13,17,28,29,31,35 11 adjusted dose per TDM and PK calculation 16,22-24,27,32-34,36,38,39 and the remaining studies focused on whole vancomycin PK dosing and monitoring process. 25,26,30,37 Vancomycin was infused intermittently in 19 studies and continuously in 1 study, 31 and the route of administration was not restricted in the outlying study. 34 A summary description of the studies is shown in Table 1.…”

“…Four studies reported time to target trough concentration. 25,26,37,39 Cardile et al 26 found that PK calculation based on patients’ height, weight, and serum creatinine to give initial dosage could decrease the time to target concentration (median [interquartile range] = 3.0 [2.0, 3.0] days vs 5.0 [2.0, 7.0] days; P < 0.001) compared with physician-guided empirical dosing. 26 Truong et al 39 showed that time to goal trough attainment for the PK and traditional groups was 54.0 ± 35.4 hours and 74.4 ± 45.7 hours, respectively ( P = 0.04).…”

“…Twelve studies that included 3407 patients reported nephrotoxicity. 13,16,17,22,26,29,30,32,36-39 The specific definitions are summarized in Supplemental Table S8. Pooled data from 11 studies demonstrated that individualized dosing via PK tools could significantly decrease the risk of nephrotoxicity (RR = 0.57, 95% CI = 0.46-0.71, P < 0.00001; Figure 4).…”