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.
OBJECTIVE
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 semi-mechanistic pharmacokinetic/pharmacodynamic model to characterize the quantitative pharmacology of LY2835219, a CDK4/6 inhibitor, in xenograft tumors.


METHODS
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 α, 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.
Authors' Affiliations: Eli Lilly and Company, Windlesham, United Kingdom; and tate_sonya@network.lilly.com.
Sonya C
SC
Tate
Eli Lilly and Company, Indianapolis, Indiana.
Shufen
S
Cai
Eli Lilly and Company, Indianapolis, Indiana.
Rose T
RT
Ajamie
Eli Lilly and Company, Indianapolis, Indiana.
Teresa
T
Burke
Eli Lilly and Company, Indianapolis, Indiana.
Richard P
RP
Beckmann
Eli Lilly and Company, Indianapolis, Indiana.
Edward M
EM
Chan
Eli Lilly and Company, Indianapolis, Indiana.
Alfonso
A
De Dios
Authors' Affiliations: Eli Lilly and Company, Windlesham, United Kingdom; and.
Graham N
GN
Wishart
Eli Lilly and Company, Indianapolis, Indiana.
Lawrence M
LM
Gelbert
Authors' Affiliations: Eli Lilly and Company, Windlesham, United Kingdom; and.
Damien M
DM
Cronier
D000284:Administration, Oral; D000631:Aminopyridines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000631:Aminopyridines; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; C000590451:abemaciclib; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6