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