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

Ji Y, Huth F, Wang C, Schiller H, Combes FP, Crown J, Fasching P, Zarate JP, Untch M (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Pharmaceuticals MDPI

Book Volume: 19

Article Number: 461

Journal Issue: 3

DOI: 10.3390/ph19030461

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Authors with CRIS profile

Peter Fasching Professur für Translationale Frauenheilkunde und Geburtshilfe

Additional Organisation(s)

Tumorzentrum der Universität Erlangen-Nürnberg

Involved external institutions

Novartis AG CH Switzerland (CH) St Vincent's University Hospital IE Ireland (IE) HELIOS Kliniken DE Germany (DE)

How to cite

APA:

Ji, Y., Huth, F., Wang, C., Schiller, H., Combes, F.P., Crown, J.,... Untch, M. (2026). Physiologically-Based Pharmacokinetics of Ribociclib Drug–Drug Interactions and Organ Impairment Pharmacokinetics in Early Breast Cancer. Pharmaceuticals, 19(3). https://doi.org/10.3390/ph19030461

MLA:

Ji, Yan, et al. "Physiologically-Based Pharmacokinetics of Ribociclib Drug–Drug Interactions and Organ Impairment Pharmacokinetics in Early Breast Cancer." Pharmaceuticals 19.3 (2026).

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