An integrated assessment of the ADME properties of the CDK4/6 Inhibitor ribociclib utilizing preclinical in vitro, in vivo, and human ADME data

Abstract

Ribociclib (LEE011, Kisqali ®) is a highly selective small molecule inhibitor of cyclindependent kinases 4 and 6 (CDK4/6), which has been approved for the treatment of advanced or metastatic breast cancer. A human ADME study was conducted in healthy male volunteers following a single oral dose of 600 mg [ 14 C]-ribociclib. Mass balance, blood and plasma radioactivity, and plasma ribociclib concentrations were measured. Metabolite profiling and identification was conducted in plasma, urine, and feces. An assessment integrating the human ADME results with relevant in vitro and in vivo non-clinical data was conducted to provide an estimate of the relative contributions of various clearance pathways of the compound. Ribociclib is moderately to highly absorbed across species (approx. 59% in human), and is extensively metabolized in vivo, predominantly by oxidative pathways mediated by CYP3A4 (ultimately forming N-demethylated metabolite M4) and, to a lesser extent, by FMO3 (N-hydroxylated metabolite M13). It is extensively distributed in rats, based on QWBA data, and is eliminated rapidly from most tissues with the exception of melanin-containing structures. Ribociclib passed the placental barrier in rats and rabbits and into milk of lactating rats. In human, 69.1% and 22.6% of the radiolabeled dose were excreted in feces and urine, respectively, with 17.3% and 6.75% of the 14 C dose attributable to ribociclib, respectively. The remainder was attributed to numerous metabolites. Taking into account all available data, ribociclib is estimated to be eliminated by hepatic metabolism (approx. 84% of total), renal excretion (7%), intestinal excretion (8%), and biliary elimination (1%). K E Y W O R D SADME, human, Kisquali, preclinical, Ribociclib

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

“…First, the PBPK model in HVs was built based on the available physicochemical, nonclinical absorption, distribution, metabolism, and excretion (ADME; both in vitro and preclinical), and clinical data derived from HVs from study A2101 and A2102 (human ADME study after single oral dose of 600 mg [ 14 C] ribociclib). 4 Model building process, model parameters, and simulation details are described in Figures 1, 2, Supplementary Document SA, Tables S1 and S2. The initial PBPK model based on the in vitro inhibition parameters of ribociclib overpredicted ribociclib CYP3A DDI potential on midazolam.…”

“…with or without food for 21 consecutive days, followed by 7 days off treatment, with option for dose reduction to 400 and 200 mg. 2,3 Ribociclib is a substrate of CYP3A4 and is also metabolized to a minor extent by flavin-containing monooxygenase 3 (FMO3). 4 Concurrent use of drugs that modulate CYP3A metabolism may potentially alter ribociclib exposure and, hence, appropriate ribociclib dosing recommendations are required to ensure therapeutic exposure is maintained. Similarly, care needs to be taken to avoid overexposure for drugs that are CYP3A substrates, for which ribociclib can act as an inhibitor.…”

Evaluation of Absolute Oral Bioavailability and Bioequivalence of Ribociclib, a Cyclin‐Dependent Kinase 4/6 Inhibitor, in Healthy Subjects

“…Cyclin‐dependent kinase 4 and 6 (CDK4/6) inhibition is an effective mechanism of action that, in combination with endocrine therapy (ET), has become the standard of care for patients with hormone receptor‐positive (HR+), human epidermal growth factor receptor‐2‐negative (HER2–) advanced or metastatic breast cancer (ABC) 1 . Ribociclib (LEE011, molecular structure as published in James et al, 2020) 2,3 is an orally bioavailable, selective, and potent 4,5 small‐molecule dual inhibitor of CDK4/cyclin‐D1 and CDK6/cyclin‐D3 enzyme complexes, which are upregulated by estrogen receptors and are required for estrogen‐dependent cell proliferation 6 . It interferes with G1‐ to S‐phase cell‐cycle progression and inhibits pRb phosphorylation, which, with cyclin D1 deregulation, is associated with endocrine resistance 7 …”

“…Ribociclib also showed moderate permeability in Caco‐2 cell monolayers and high passive permeability in human hepatocytes (data on file). Ribociclib is transported by human ABCB1 (P‐gp), but not by human ABCG2 15,16 ; it has a human plasma protein binding of approximately 70% and is extensively distributed 3 . Ribociclib is excreted predominantly via hepatic elimination in humans and is primarily metabolized by cytochrome P450 (CYP) 3A4 3,17 .…”

“…Ribociclib is transported by human ABCB1 (P‐gp), but not by human ABCG2 15,16 ; it has a human plasma protein binding of approximately 70% and is extensively distributed 3 . Ribociclib is excreted predominantly via hepatic elimination in humans and is primarily metabolized by cytochrome P450 (CYP) 3A4 3,17 . LEQ803 (molecular structure published in James et al, 2020) is a major circulating metabolite of ribociclib formed via CYP3A4 and has no clinically relevant contribution to the pharmacological activity in vivo 3,18 …”