Ribociclib Drug‐Drug Interactions: Clinical Evaluations and Physiologically‐Based Pharmacokinetic Modeling to Guide Drug Labeling

Ribociclib is approved in combination with endocrine therapy as initial endocrine‐based therapy for HR‐positive and HER2‐negative advanced breast cancer. Ribociclib is primarily metabolized by CYP3A4 and, in vitro , is an inhibitor of CYP3A and CYP1A2. Ritonavir (a strong CYP3A inhibitor) increased ribociclib 400 mg single‐dose area under the plasma concentration‐time curve (AUC) by 3.2‐fold, whereas rifampin (a strong CYP3A inducer) decreased ribociclib AUC by 89% in healthy volunteers (HVs). Multiple 400 mg ribociclib doses increased midazolam (CYP3A substrate) AUC by 3.8‐fold and caffeine (CYP1A2 substrate) AUC by 1.2‐fold vs. each agent alone. A physiologically‐based pharmacokinetic (PBPK) model was developed integrating in vitro , preclinical, and clinical data of HVs and patients with cancer. Data predictions indicated that multiple 600 mg ribociclib doses increased midazolam AUC by 5.85‐fold and ritonavir increased ribociclib 600 mg multiple dose AUC by 1.31‐fold in cancer patients. Based on pharmacokinetics, safety, and efficacy data, and PBPK modeling, dosing modifications for ribociclib recommend avoiding concurrent use of strong CYP3A inhibitors/inducers, and caution regarding using CYP3A substrates with narrow therapeutic indices.