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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1420174

Exploring Pharmacokinetic Variability of Palbociclib in HR+/HER2-Metastatic Breast Cancer: A Focus on Age, Renal Function and Drug-/Gene interactions

Provisionally accepted

The final, formatted version of the article will be published soon.

    Palbociclib, an oral inhibitor of cyclin-dependent kinase 4 and 6, is approved for the treatment of metastatic breast cancer. This study investigated the influence of diverse clinical and biological factors-age, renal function, genetic variations, and comedicationsconcomitant medication (pharmacokinetic covariates)-on palbociclib pharmacokinetics. Employing a validated LC-MS/MS method, we analyzed the minimum plasma concentrations (Ctrough) of palbociclib in 68 women and determined the percentage deviations from the median Ctrough for each dosage group. Variations in a panel of ADME genes were assessed using end-point allele-specific fluorescence detection and pyrosequencing. Two distinct patient cohorts were defined based on median values of age, creatinine, and eGFR, which exhibited statistically significant differences in percentage deviations (p=0.0095; p=0.0288; p=0.0005, respectively). Homozygous carriers of the PPARA variant displayed larger positive percentage deviations compared to the other group (p=0.0292). Similarly, patients concurrently taking CYP3A and P-glycoprotein inhibitors alongside anticancer therapy exhibited significant variations (p=0.0285 and p=0.0334, respectively). Furthermore, exploring the drug-drug-gene interactions between inhibitors of CYP3A and P-glycoprotein with their respective genetic variants revealed two patient groups with statistically different percentage deviations (p=0.0075, p=0.0012, and p=0.0191, respectively). All these results shed light on the pharmacokinetic variability of palbociclib.

    Keywords: Palbociclib, metastatic breast cancer, minimum plasma concentration, Pharmacokinetic variability, pharmacokinetic covariate

    Received: 19 Apr 2024; Accepted: 15 Jul 2024.

    Copyright: © 2024 Peruzzi, Posocco, Gerratana, Nuti, Orleni, Gagno, De Mattia, Puglisi, Cecchin, Toffoli and Roncato. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Bianca Posocco, Aviano Oncology Reference Center (IRCCS), Aviano, Italy
    Giuseppe Toffoli, Aviano Oncology Reference Center (IRCCS), Aviano, Italy

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.