Ribociclib (KISQALI), a cyclin-dependent kinase 4/6 inhibitor approved for the first-line treatment of HR+/HER2– advanced breast cancer with an aromatase inhibitor, is administered with no restrictions on concomitant gastric pH-elevating agents or food intake. The influence of proton pump inhibitors (PPIs) on ribociclib bioavailability was assessed using 1) biorelevant media solubility, 2) physiologically based pharmacokinetic (PBPK) modeling, 3) noncompartmental analysis (NCA) of clinical trial data, and 4) population PK (PopPK) analysis. This multipronged approach indicated no effect of gastric pH changes on ribociclib PK and served as a platform for supporting ribociclib labeling language, stating no impact of gastric pH-altering agents on the absorption of ribociclib, without a dedicated drug–drug interaction trial. The bioequivalence of ribociclib exposure with or without a high-fat meal was demonstrated in a clinical trial. Lack of restrictions on ribociclib dosing may facilitate better patient compliance and therefore clinical benefit.