Abstract P1-14-05: Ribociclib dose recommendations for potential pharmacokinetic drug interaction and in special patient populations with organ impairment
Authors: Abdelhady AM , Samant TS , Chakraborty A , Germa C , Liu X , Umehara K-I , Huth F , Lu Y , Yang S , Quinlan M , Laisney M , Mueller-Zsigmondy M , Elmeliegy M 
Published: February 2018

Background: Ribociclib (Kisqali®) is a CDK4/6 inhibitor, recently approved in the U.S. as a first line therapy for HR+/HER2- advanced breast cancer (ABC) in combination with an aromatase inhibitor. The recommended starting dose is 600 mg/day orally (3 wks-on/1 wk-off). Ribociclib inhibits CYP3A4 and its metabolism is mostly CYP3A4-mediated. Here we evaluate the effect of food, conmeds and special patient populations on ribociclib pharmacokinetics (PK) and dose recommendations.

Methods: In vitro and clinical data (food effect, drug–drug interactions, organ impairment and Phase I/III trials) were analyzed using physiologically-based PK (PBPK), population PK (PopPK) models and non-compartmental analysis (NCA). Dose recommendations were made considering ribociclib PK, safety and efficacy data.

Food effect/Conmeds/Special populationsObjectiveResultsDose RecommendationFood effectEvaluate food effect on ribociclib PK following single oral dose (SD) 600 mg in healthy volunteers (HV)No changes in ribociclib PK when taken with foodRibociclib can be taken with or without foodGastric pH-elevating Agents-No effect of gastric pH-elevating agents on ribociclib PK (determined by PBPK, PopPK and NCA)No dose adjustment reqiuredCYP3A4 InhibitorsEvaluate effect of ritonavir on SD ribociclib PK in HVIncreased ribociclib SD Cmax (1.7-fold) and AUC (3.2-fold) with ritonavir. Overlapping predicted steady state exposure at a) 400 mg + strong inhibitors, b) 600 mg + moderate inhibitors and c) 600 mg without inhibitorsStrong inhibitors: avoid, if cannot be avoided reduce ribociclib dose to 400 mg -Moderate inhibitors: no dose adjustmentCYP3A4 InducersEvaluate effect of rifampicin on SD ribociclib PK in HVReduced ribociclib SD AUCinf (89%) with rifampicin. Overlapping predicted steady state exposure with/without moderate inducersStrong inducers: avoid -Moderate inducers: no dose modificationCYP3A4 SubstratesEvaluate effect of multiple dose ribociclib 400 mg on midazolam PK in HVIncreased midazolam Cmax (2-fold) and AUCinf (3.8-fold)No dose adjustment for ribociclib. Caution with CYP3A substrates with narrow therapeutic indexCYP1A2 SubstratesEvaluate effect of multiple dose ribociclib 400 mg on caffeine PK in HVNo effect of ribociclib on caffeineNo dose adjustmentHepatic Impairment (HI)Evaluate ribociclib 400 mg SD PK in non-cancer subjects with varying degrees of HISimilar exposure in mild and ∼30% higher in moderate and severe HI compared to normal hepatic functionMild HI: No dose adjustment Moderate & severe HI: reduce starting dose to 400 mgRenal Impairment (RI)Evaluate ribociclib 400 mg SD PK in non-cancer subjects with severe RI (ongoing)No effect of mild and moderate RI on ribociclib exposure (PopPK), study in severe RI ongoing-Mild or moderate RI: No dose adjustment - Severe RI: results pending

Conclusions: Ribociclib 600 mg daily (3 wks-on/1 wk-off) has shown clinical benefit in treatment of HR+/HER2- ABC with a manageable safety profile. Ribociclib can be conveniently administered without regard to food intake or gastric pH-elevating agents. Appropriate ribociclib dose recommendations with concomitant medications or organ function impairment were made considering ribociclib PK, safety and efficacy.

Citation Format: Abdelhady AM, Samant TS, Chakraborty A, Germa C, Liu X, Umehara K-I, Huth F, Lu Y, Yang S, Quinlan M, Laisney M, Mueller-Zsigmondy M, Elmeliegy M. Ribociclib dose recommendations for potential pharmacokinetic drug interaction and in special patient populations with organ impairment [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-14-05.