Ribociclib Bioavailability Is Not Affected by Gastric pH Changes or Food Intake: In Silico and Clinical Evaluations.

Authors: Samant TS, Dhuria S, Lu Y, Laisney M, Yang S, Grandeury A, Mueller-Zsigmondy M, Umehara K, Huth F, Miller M, Germa C, Elmeliegy M
Publication: Clin Pharmacol Ther
Keywords: absorption, ddI, drug labeling, drug–drug interaction, gastric pH, PBPK modeling, PPI, stomach
Software: GastroPlus®

Abstract

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) non-compartmental analysis (NCA) of clinical trial data, and (4) population PK (PopPK) analysis. This multi-pronged 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.