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

Abstract

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.

Ribociclib Population Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Analysis of Neutrophils in Cancer Patients

“…The evaluation of weak CYP3A4/5 inhibitors was exploratory due to limitation of the analysis (Supplement 2). The results showed a lack of effect of weak CYP3A4/5 inhibitors consistent with the conclusion from physiologically based PK modeling in patients with cancer 42 . Overall, the PK or exposure (AUC) of ribociclib was not affected by the covariates evaluated; therefore, no dose adjustment is needed for subpopulations defined by these covariates.…”

Pharmacokinetics of Ribociclib in Subjects With Hepatic Impairment

“…Both in vitro and in vivo human studies indicate that ribociclib is excreted primarily via hepatic elimination and is metabolized mainly by cytochrome P450 (CYP) 3A4 (63%) with smaller contribution by flavin‐containing monooxygenase 3 (FMO3; 16%) 16,18 . In addition, around 7% of ribociclib elimination is by renal excretion and 8% is by intestinal excretion 16 .…”

“…In addition, around 7% of ribociclib elimination is by renal excretion and 8% is by intestinal excretion 16 . LEQ803 is a major metabolite of ribociclib formed via CYP3A4 and has no clinically relevant contribution to the pharmacologic activity in vivo 18 . Extensive metabolism of ribociclib means that unchanged drug accounts for only 17.3% and 12.1% of the administered dose found in feces and urine, respectively.…”

“…The dose selected for this study is a single dose of 400 mg ribociclib for safety consideration in hepatic impaired subjects. Ribociclib was administered as a single dose (400 mg or 600 mg) or multiple doses (400 mg for 8 days) in healthy subjects and demonstrated to be safe 15,17,21 . In cancer patients, treatment with ribociclib single agent was given at repeat doses ranging from 50 mg to 1200 mg, with 900 mg as the maximum tolerated dose, and ribociclib accumulated approximately 2‐ to 3‐fold at steady state after daily dosing 22 .…”

The Changing Face of Oncology Research, Drug Development, and Clinical Practice: Toward Patient‐Focused Precision Therapeutics

“…15 Physiologically-based pharmacokinetic modeling and simulation has steadily driven efficiency in evaluating intrinsic and extrinsic factor effects in drug development to inform dosing and administration across clinical contexts of use, as elegantly demonstrated with the cyclin-dependent kinase 4/6 inhibitor ribociclib. 16 Of note, our understanding of sources of variability in the clinical pharmacology of therapeutics continues to evolve, illustrated in a survey of the impact of hepatic impairment on pharmacokinetics of monoclonal antibodies. 17 It is evident that the practice of clinical pharmacology in the era of novel therapeutic modalities (like gene and cell therapies, oncolytic viruses, and personalized cancer vaccines) will warrant unique considerations and the development of new approaches.…”