External evaluation of intravenous vancomycin population pharmacokinetic models in adults receiving high-flux intermittent haemodialysis

Aims: Patients undergoing haemodialysis (HD) are at greater risk of methicillin-resistant Staphylococcus aureus infections requiring intravenous vancomycin. Close vancomycin therapeutic drug monitoring is warranted in HD patients as renal clearance is the primary elimination pathway. Clinically, population pharmacokinetics (popPK) model-informed dosing is commonly used. This study aimed to perform an external evaluation of published vancomycin popPK models developed for adults undergoing high-flux intermittent HD, and to create a dosing nomogram derived from the model that performed best.

Methods: A literature review was conducted through PubMed and EMBASE to identify relevant popPK models. an external dataset was collected retrospectively from patients of 2 healthcare centres in Quebec, Canada. Selected models were implemented in NONMEM (v7.5; ICON Development Solutions). Predictive performance was assessed through prediction and simulation-based diagnostics.

Results: In total, 2386 vancomycin concentrations were collected from 274 patients and 476 antibiotic courses. Four vancomycin popPK models were selected for evaluation. None of the models demonstrated overall satisfactory or clinically acceptable predictive performance. Nonetheless, Bae et al.'s model performed best with a median prediction error of 16.25% and median absolute prediction error of 34.66%. Different predictive performance was also observed for vancomycin concentrations from samples collected during and between HD sessions.

Conclusion: All evaluated models presented poor overall predictive performance. Further studies are required, through existing popPK model parameter re-estimation or new model development, to adequately describe vancomycin pharmacokinetics for our high-flux intermittent HD patient cohort.