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

• Published in: Frontiers in pharmacology 2024-09, Vol.15, p.1420174
• Main Authors: Peruzzi, Elena, Posocco, Bianca, Gerratana, Lorenzo, Nuti, Margherita, Orleni, Marco, Gagno, Sara, De Mattia, Elena, Puglisi, Fabio, Cecchin, Erika, Toffoli, Giuseppe, Roncato, Rossana
• Format: Article
• Language: English
• Subjects: drug-drug interactions; metastatic breast cancer; minimum plasma concentration; palbociclib; pharmacokinetic covariate; pharmacokinetic variability
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2024.1420174

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 ( )-on palbociclib pharmacokinetics. Employing a validated LC-MS/MS method, we analyzed the minimum plasma concentrations (C ) of palbociclib in 68 women and determined the percentage deviations from the median C 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 ( = 0.0095, = 0.0288, and = 0.0005, respectively). Homozygous carriers of the variants displayed larger positive percentage deviations than the other group ( = 0.0292). Similarly, patients concurrently taking CYP3A and P-glycoprotein inhibitors alongside anticancer therapy exhibited significant variations ( = 0.0285 and = 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 ( = 0.0075, = 0.0012, and = 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.