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Machine-Learning Exploration of Exposure-Effect Relationships of Cisplatin in Head and Neck Cancer Patients

Background: Cisplatin is a pivotal drug in the treatment of head and neck cancer, and personalized dosage should help the preservation of an optimal toxicity–efficacy ratio. Methods: We analyzed the exposure-effect relationships of 80 adult patients with head and neck cancers and treated with standa...

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Detalles Bibliográficos
Autores principales: Cauvin, Céleste, Bourguignon, Laurent, Carriat, Laure, Mence, Abel, Ghipponi, Pauline, Salas, Sébastien, Ciccolini, Joseph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9699030/
https://www.ncbi.nlm.nih.gov/pubmed/36432700
http://dx.doi.org/10.3390/pharmaceutics14112509
Descripción
Sumario:Background: Cisplatin is a pivotal drug in the treatment of head and neck cancer, and personalized dosage should help the preservation of an optimal toxicity–efficacy ratio. Methods: We analyzed the exposure-effect relationships of 80 adult patients with head and neck cancers and treated with standard Cisplatin-based regimen administered as three-hour infusion. Individual pharmacokinetics (PK) parameters of Cisplatin were identified using a Bayesian approach. Nephrotoxicity and ototoxicity were considered as typical Cisplatin-related toxicities according to Common Terminology Criteria for Adverse Events (CTCAE) standards. Efficacy was evaluated based upon Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Up to nine different machine-learning algorithms were tested to decipher the exposure-effect relationships with Cisplatin. Results: The generalized linear model was the best algorithm with an accuracy of 0.71, a recall of 0.55 and a precision of 0.75. Among the various metrics for exposure (i.e., maximal concentration (Cmax), area-under-the-curve (AUC), trough levels), Cmax, comprising a range between 2.4 and 4.1 µg/mL, was the best one to be considered. When comparing a consequent, model-informed dosage with the standard dosage in 20 new patients, our strategy would have led to a reduced dosage in patients who would eventually prove to have severe toxicities while increasing dosage in patients with progressive disease. Conclusion: Determining a target Cmax could pave the way for PK-guided precision dosage with Cisplatin given as three-hour infusion.