Clinical And Pharmacokinetic Evaluation Of Optimal Monitoring Parameters And Sampling Schemes For Vancomycin Therapeutic Drug Monitoring In Qatar

Abstract

Background: Therapeutic drug monitoring (TDM) of vancomycin has been proven to maximize therapeutic outcomes and minimize toxicity when conducted appropriately. The quality of vancomycin TDM services in many settings remains to be explored. Vancomycin still poses many questions regarding its clinical pharmacokinetic parameters, optimal dosing, and TDM strategies in unstudied populations. Objectives: This project comprised three distinct sequential phases. Phase I aimed to evaluate the appropriateness of routine vancomycin TDM service in Qatar and its impact on clinical outcomes. Phase II aimed to evaluate the relationship between vancomycin 24-hr-AUC/MIC ratios and cure; and to compare the clinical outcomes between peak-trough-based and trough-onlybased vancomycin TDM approaches. Phase III aimed to determine vancomycin population pharmacokinetics considering patient-specific covariates and to assess the need for vancomycin dosing nomograms that are specific to Qatar’s population. Methods: Phase I was a retrospective chart review that was conducted on adult non-dialysis vancomycin TDM cases electronically documented between January 2014 and August 2016 in Al-Wakrah Hospital (AWH), Al- Khor Hospital (AKH), and Hamad General Hospital (HGH). Evidence-based criteria were applied to evaluate TDM appropriateness. Descriptive and inferential statistical analyses were applied using SPSS v.23. Phase II was a multicenter pragmatic parallel prospective randomized controlled trial (RCT) that was conducted from February 2016 to September 2016 in HGH, AWH and AKH. Adult non-dialysis patients who were initiated on vancomycin treatment were randomized to intervention arm (peak-trough-based vancomycin TDM) or control arm (trough-only-based vancomycin TDM). Multiple steady-state vancomycin blood samples were obtained for AUC determination. 24-hr-AUC calculation was conducted using NONMEM version 7.3 (ICON,USA) and PDx-Pop version 5.2 (ICON,USA), utilizing the population pharmacokinetic model developed in Phase III. Descriptive, inferential, and CART statistical analyses were applied using SPSS v.23. Phase III was a population pharmacokinetic analysis that was conducted based on the principles of non-linear-mixed-effects-modeling. Internal validation of the final model was applied by bootstrap analysis of 500 data replicates. The agreement between the final parameter estimates, 95%confidence intervals of the developed final model and the bootstrap results were compared. To evaluate the need for population-specific dosing nomograms, the generated population parameter estimates were compared against literature reported values in similar populations. Phase III procedures were conducted using NONMEM v.7.3, (ICON,USA) and PDx-Pop v.5.2 (ICON,USA). Results: Phase I: Two hundred eight vancomycin TDM cases involving 99 patients were evaluated. Most of the evaluated TDM cases (90.4%, n=188) were inappropriately conducted. The indications for TDM requests were appropriate in most of the cases (77.4%, n=161). Most of the blood samples were collected at incorrect times (70.7%, n=147), and incorrectly labelled (81.7%, n=170). Overall, the actual sampling times revealed that most vancomycin blood samples (61.5%, n=128) corresponded to vancomycin random concentrations. Furthermore, high rates of inappropriate post- analytical actions were recorded (65.9%, n=137). Inappropriate compared to appropriate vancomycin TDM practices were associated with significantly lower therapeutic cures [47.3% vs .75%; p-value=0.009] and longer hospitalizations [median[IQR]: 26[31] vs. 13[47.7] days; p-value=0.103]. All patients who experienced neutropenia (100%, n=6) received inappropriate vancomycin TDM service. Similarly, of all patients who experienced nephrotoxicity, 84.6% (n=11) received inappropriate vancomycin TDM service. Phase II: Sixty-five patients were enrolled in the RCT [trough-only-group:35 patients vs. peak-trough-group:30 patients]. Peak-trough-based vancomycin TDM was significantly associated with higher therapeutic cure rates compared to control group [76.7% vs .48.6%; p-value=0.02]. Compared to the control group, peak-trough-based vancomycin TDM recipients required less average vancomycin single doses and total daily doses by 370mg/dose and 927mg/day, respectively [p-value<0.05]. Similarly, trough-only-based vancomycin TDM recipients required higher cumulative vancomycin doses versus the intervention group [median[IQR]: 19500[25860] mg vs. 13250[14925] mg; p-value>0.05]. CART identified creatinine clearance(CrCl), 24-hr-AUC and TDM approach as significant determinants of therapeutic outcomes. All patients with CrCl≤7.85L/hr who achieved 24- hr- AUC≤1255.98mg.hr/L and received peak-trough-based vancomycin TDM achieved clinical success [100%, n=19]. In contrast, patients with CrCl≤7.85L/hr who maintained 24-hr-AUC≤1255.98mg.hr/L but received trough-only-based vancomycin TDM experienced 29.4% (n=5) failure rates. Maintenance of 24-hr-AUC>564.117mg.hr/L was identified as the breakpoint of cure in trough-only-based TDM recipients [84.6%, n=11]. Phase III: A total of 769 vancomycin blood concentrations obtained from 156 subjects were analyzed. A two-compartment model with a proportional residual error and between-subject variability modeled on clearance (Cl), central compartment volume of distribution (Vc) and intercompartmental clearance (Q) best described vancomycin disposition. The physiologic parameters Cl and Vc, were estimated with good precision [Cl:5.23L/h, 95%CI: 4.72-5.74; Vc:44L, 95%CI: 37.7-50.3]. CrCl and age were significant covariates in the final model (p-value<0.01). Interindividual variability for Cl, Vc and Q was 38.9%, 42.7%, and 97% in the final model, respectively. Fixed effects parameters were estimated with reasonable precision and lied within 95%CI of bootstrap analysis. The population parameter estimates were similar to literature reported 2-compartment model estimates in adult non-dialysis patients. Conclusion: This work suggests that the improvement of the quality of vancomycin TDM practices, maintenance of a 24-hr-AUC between 564.117- 1255.98 mg.hr/L, and the implementation of peak-trough-based vancomycin TDM, are three main strategies that will potentially improve health-care outcomes associated with vancomycin treatment. The findings have important implications on developing strategies that will improve rational TDM practices in Qatar, the Middle East region and possibly worldwide