AUTHOR=Peruzzi Elena , Posocco Bianca , Gerratana Lorenzo , Nuti Margherita , Orleni Marco , Gagno Sara , De Mattia Elena , Puglisi Fabio , Cecchin Erika , Toffoli Giuseppe , Roncato Rossana 

TITLE=Exploring pharmacokinetic variability of palbociclib in HR+/HER2- metastatic breast cancer: a focus on age, renal function, and drug–gene interactions

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1420174

DOI=10.3389/fphar.2024.1420174

ISSN=1663-9812

ABSTRACT=<p>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 concomitant medications (<italic>pharmacokinetic covariates</italic>)—on palbociclib pharmacokinetics. Employing a validated LC-MS/MS method, we analyzed the minimum plasma concentrations (C<sub>trough</sub>) of palbociclib in 68 women and determined the percentage deviations from the median C<sub>trough</sub> for each dosage group. Variations in a panel of absorption, distribution, metabolism, and excretion (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 (<italic>p</italic> = 0.0095, <italic>p</italic> = 0.0288, and <italic>p</italic> = 0.0005, respectively). Homozygous carriers of the <italic>PPARA</italic> variants displayed larger positive percentage deviations than the other group (<italic>p</italic> = 0.0292). Similarly, patients concurrently taking CYP3A and P-glycoprotein inhibitors alongside anticancer therapy exhibited significant variations (<italic>p</italic> = 0.0285 and <italic>p</italic> = 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 (<italic>p</italic> = 0.0075, <italic>p</italic> = 0.0012, and <italic>p</italic> = 0.0191, respectively). These results could help address cases where pharmacokinetic covariates or subclinical conditions impair palbociclib adherence or response, aiming to offer tailored dosing strategies or monitoring for individual patients.</p>