Physiologically-Based Pharmacokinetics of Ribociclib Drug–Drug Interactions and Organ Impairment Pharmacokinetics in Early Breast Cancer

<b>Background:</b> Ribociclib, initially approved for HR+/HER2- advanced breast cancer (ABC) at a 600 mg dose, was recently approved for HR+/HER2- early breast cancer (EBC) at a 400 mg dose based on the NATALEE trial. Differences in dose and patient population warrant reassessment of ribociclib drug-drug interactions (DDIs) and the impact of hepatic or renal impairment (HI/RI) in EBC patients to guide co-medication management and subpopulation dose recommendations. <b>Methods:</b> Physiologically-based pharmacokinetic (PBPK) modeling based on a healthy volunteer population was conducted to assess ribociclib DDIs with CYP3A4 substrates/modulators in patients with EBC. Subgroup analysis from NATALEE assessed HI/RI impact on ribociclib PK in EBC patients. Existing data from ABC/advanced cancer patients and non-cancer subjects were also integrated to inform dose recommendations for EBC subpopulations. <b>Results:</b> PBPK modeling predicted that ritonavir or erythromycin (strong and moderate CYP3A4 inhibitors) would increase ribociclib steady-state area under the concentration-time curve (AUC) by 1.84-fold or show no meaningful impact, respectively. Steady-state ribociclib AUC was estimated to decrease by 83% and 74% with rifampicin and efavirenz, strong and moderate CYP3A4 inducers, respectively. Ribociclib was estimated to increase CYP3A4 substrate midazolam exposure by 280%. Mild HI or mild/moderate RI did not show an apparent impact on ribociclib PK. <b>Conclusions:</b> Using relevant data and methodology for EBC patients, this analysis informed the approved ribociclib label of no dose adjustment for EBC patients with concomitant use of a moderate CYP3A inhibitor, any degree of HI, or mild/moderate RI, and a reduced 200 mg dose for patients with concomitant use of a strong CYP3A inhibitor or severe RI.