Semi-Mechanistic Pharmacokinetic/Pharmacodynamic Modeling of the Antitumor Activity of LY2835219, a New Cyclin-Dependent Kinase 4/6 Inhibitor, in Mice Bearing Human Tumor Xenografts

Abstract

Purpose: Selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) represents a promising therapeutic strategy. However, despite documented evidence of clinical activity, limited information is available on the optimal dosing strategy of CDK4/6 inhibitors. Here, we present an integrated semimechanistic pharmacokinetic/pharmacodynamic model to characterize the quantitative pharmacology of LY2835219, a CDK4/6 inhibitor, in xenograft tumors.Experimental Design: LY2835219 plasma concentrations were connected to CDK4/6 inhibition and cell-cycle arrest in colo-205 human colorectal xenografts by incorporating the biomarkers, phospho-(ser780)-Rb, topoisomerase II a, and phosphohistone H3, into a precursor-dependent transit compartment model. This biomarker model was then connected to tumor growth inhibition (TGI) by: (i) relating the rate of tumor growth to mitotic cell density, and (ii) incorporating a concentration-dependent mixed cytostatic/ cytotoxic effect driving quiescence and cell death at high doses. Model validation was evaluated by predicting LY2835219-mediated antitumor effect in A375 human melanoma xenografts.Results: The model successfully described LY2835219-mediated CDK4/6 inhibition, cell-cycle arrest, and TGI in colo-205, and was validated in A375. The model also demonstrated that a chronic dosing strategy achieving minimum steady-state trough plasma concentrations of 200 ng/mL is required to maintain durable cell-cycle arrest. Quiescence and cell death can be induced by further increasing LY2835219 plasma concentrations.Conclusions: Our model provides mechanistic insight into the quantitative pharmacology of LY2835219 and supports the therapeutic dose and chronic dosing strategy currently adopted in clinical studies.

Tumor Static Concentration Curves in Combination Therapy

“…One of the most commonly applied experimental models is the tumor growth inhibition (TGI) model (10)(11)(12)(13). The TGI model balances model complexity with data availability.…”

Targeting CDK6 in cancer: State of the art and new insights

“…Mechanistically, these drug candidates inhibit CDK4/6, halt Rb phosphorylation and arrest G1 cell cycle progression of cancer cells. 51,[90][91][92][93] PD0332991 has also demonstrated to cause almost identical senescence phenotypes as the endogenous CDK inhibitors p16 INK4a and p21 Cip1 do. 94 PD0332991 is a pyridopyrimidine derivative ( Table 2) developed by Pfizer with relative high level of selectivity toward CDK4 and CDK6.…”

Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non–Small Cell Lung Cancer, and Other Solid Tumors

“…Consistent with its activity against CDK4 and CDK6, abemaciclib inhibits RB phosphorylation and leads to G 1 arrest in RB-profi cient cell lines ( 21 ). In a colorectal cancer xenograft model used to develop an integrated pharmacokinetic/pharmacodynamic model, abemaciclib can be dosed orally on a continuous schedule to achieve sustained target inhibition and demonstrates not only durable cellcycle inhibition but also single-agent antitumor activity ( 21,22 ). Tumor growth inhibition is observed in multiple other human cancer xenograft models, including those derived from non-small cell lung cancer (NSCLC), melanoma, glioblastoma, and mantle cell lymphoma (21)(22)(23).…”

“…In a colorectal cancer xenograft model used to develop an integrated pharmacokinetic/pharmacodynamic model, abemaciclib can be dosed orally on a continuous schedule to achieve sustained target inhibition and demonstrates not only durable cellcycle inhibition but also single-agent antitumor activity ( 21,22 ). Tumor growth inhibition is observed in multiple other human cancer xenograft models, including those derived from non-small cell lung cancer (NSCLC), melanoma, glioblastoma, and mantle cell lymphoma (21)(22)(23). Abemaciclib distributes across the blood-brain barrier and prolongs survival in an intracranial glioblastoma xenograft model ( 24 ), suggesting potential effi cacy against primary and metastatic tumors involving the central nervous system.…”