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

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 (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 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 (p = 0.0095, p = 0.0288, and p = 0.0005, respectively). Homozygous carriers of the PPARA variants displayed larger positive percentage deviations than 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). 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.