Toward Model-Based Informed Precision Dosing of Vancomycin in Hematologic Cancer Patients: A First Step.

Background and objective: There is no consensus on the optimal vancomycin dose to achieve pharmacokinetic/pharmacodynamic (PK/PD) target in patients with hematologic cancer or in hematopoietic stem cell transplant (HSCT) recipients. A 24-h area under the concentration-time curve (AUC) >400 mg*h/L must be achieved early for successful treatment of severe methicillin-resistant Staphylococcus aureus (MRSA) infections. Current nomograms derived from general population data are not sufficiently accurate to allow AUC-based model-informed precision dosing. The objective of this study was to characterize vancomycin PK in patients with hematologic cancer or in HSCT recipients and to develop a model-informed dosing tool based on PK/PD target requirements.

Methods: Pooled retrospective and prospective vancomycin serum concentrations were analyzed using NONMEM^® to evaluate the performance of previously published population PK (popPK) models built from hematologic cancer datasets and to develop a novel Bayesian PK model. Patients' characteristics and clinical data were tested as potential covariates. The popPK model was validated internally and externally. Predictions of vancomycin concentrations for different dosing regimens were made using Monte-Carlo simulations, and a nomogram strategy was proposed according to selected probability of target attainment (PTA).

Results: The predictive performance of the published popPK models was found to be suboptimal for our population. A novel popPK model was developed using 240 vancomycin concentrations (60 patients). A two-compartment structural model with an additive error model best described the data. Ideal body weight and estimated glomerular filtration rate (eGFR) [Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)] were selected as covariates for volume of distribution (V) and clearance (CL). Bootstrapping confirmed the stability and precision of the popPK parameters. The volume of distribution was V1 = 46.8 L and V2 = 56.1 L, while CL = 5.63 L/h. External validation using 107 vancomycin concentrations (24 patients) demonstrated the predictivity of the model. A nomogram was developed to reach minimally PTA >50% for 400 < AUC < 600 mg*h/L.

Conclusion: To our knowledge, this study provides the first model-informed AUC-based strategy in North American hematologic cancer patients with or without HSCT. The resulting nomogram generated provides a simplified approach to improving the accuracy of initial vancomycin dosing in this population.