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

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Abstract

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.

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Acknowledgements

The authors thank Michel Savoie for his precious feedback at every step of this project and for reviewing the manuscript. The authors also thank Asma Ghorbaniyanamirkhiz and Danielle Fany Ngontié Tcheudjio for participating in protocol writing, subject recruitment, and data collection; Sandrine Sinju-Caron for participating in data collection; and Bogdan Andrei Panait for his participation in the recruitment of the prospective subjects. Amélie Marsot acknowledges support from the Fonds de Recherche du Québec-Santé (FRQS) Research Scholars-Junior 1 (Young Researcher Establishment) Career Scholarship.

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Authors and Affiliations

  1. Faculté de Pharmacie, Université de Montréal, Montréal, QC, Canada

    Jessica Le Blanc, Denis Projean, Sandra Savignac, Sophie Léveillé, Marie-Pier Ducas & Amélie Marsot

  2. Centre intégré universitaire de santé et de services sociaux de l’Est-de-l’Île-de-Montréal (Département de Pharmacie), Montréal, QC, Canada

    Jessica Le Blanc, Denis Projean, Sandra Savignac, Sophie Léveillé, Marie-Pier Ducas & Annie Brisebois-Boyer

  3. Centre de Recherche, CHU Sainte-Justine, Montréal, QC, Canada

    Amélie Marsot

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Correspondence to Amélie Marsot.

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Funding

Amélie Marsot received financial support from the Fonds de Recherche du Québec-Santé (FRQS) Research Scholars-Junior 1 (Young Researcher Establishment) Career Scholarship.

Conflicts of Interest

Jessica Le Blanc, Denis Projean, Sandra Savignac, Sophie Léveillé, Marie-Pier Ducas, Annie Brisebois-Boyer, and Amélie Marsot declare they have no competing interests associated with this publication.

Ethics Approval

This clinical trial was approved by the local human research and ethics committee (REB) [CIUSSS de l’Est-de-l’Île-de-Montréal - 2021-2482] and was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines.

Consent to Participate and for Publication

All participants in the prospective cohort provided written consent to participate. Authorization from the local REB was obtained to collect data retrospectively from chart review.

Data Availability

Individual patient data from Maisonneuve-Rosemont Hospital is not publicly accessible.

Code Availability

The code is available from the corresponding author on reasonable request.

Authors’ Contributions

Conception and design: All authors. PK model development and related computational analysis: AM. Statistical analysis: JLB, DP, AM. Data interpretation: All authors. Writing – original draft preparation: DP, JLB, AM, AB. Writing – review and editing: All authors.

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Le Blanc, J., Projean, D., Savignac, S. et al. Toward Model-Based Informed Precision Dosing of Vancomycin in Hematologic Cancer Patients: A First Step. Clin Pharmacokinet 63, 183–196 (2024). https://doi.org/10.1007/s40262-023-01329-0

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