Development and Application of a Mechanistic Population Modeling Approach to Describe Abemaciclib Pharmacokinetics

Emmanuel Chigutsa; Siva Rama Prasad Kambhampati; Amanda Karen Sykes; Maria M Posada; Jan-Stefan van der Walt; P Kellie Turner

doi:10.1002/psp4.12544

Development and Application of a Mechanistic Population Modeling Approach to Describe Abemaciclib Pharmacokinetics

CPT Pharmacometrics Syst Pharmacol. 2020 Sep;9(9):523-533. doi: 10.1002/psp4.12544. Epub 2020 Aug 13.

Authors

Emmanuel Chigutsa¹, Siva Rama Prasad Kambhampati¹, Amanda Karen Sykes¹, Maria M Posada², Jan-Stefan van der Walt¹, P Kellie Turner¹

Affiliations

¹ Global PK/PD & Pharmacometrics, Eli Lilly and Company, Indianapolis, Indiana, USA.
² Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana, USA.

Abstract

Abemaciclib is an oral anticancer drug that inhibits cyclin dependent kinases 4 and 6 and is metabolized by cytochrome P450 3A in the intestines and liver to active metabolites. The objectives were (1) to develop a mechanistic model to characterize the pharmacokinetics (PK) of the active moieties and investigate the effect of patient factors and (2) apply the model to dat from two phase III breast cancer trials of abemaciclib in combination with endocrine therapy. To develop the model, data from seven phase I studies and two phase II studies including 421 patients with cancer and 65 healthy individuals were pooled for nonlinear mixed effects modeling. The PK was similar between patients and healthy subjects, and the effects of diarrhea, formulation, race, and patient covariates on exposure were negligible. Application of the model confirmed its predictive performance and that abemaciclib PK did not change when coadministered with endocrine therapy.

Publication types

Clinical Trial, Phase III
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Aminopyridines / administration & dosage
Aminopyridines / pharmacokinetics*
Aminopyridines / therapeutic use
Antineoplastic Agents, Hormonal / administration & dosage
Antineoplastic Agents, Hormonal / therapeutic use
Antineoplastic Combined Chemotherapy Protocols
Benzimidazoles / administration & dosage
Benzimidazoles / pharmacokinetics*
Benzimidazoles / therapeutic use
Breast Neoplasms / drug therapy*
Case-Control Studies
Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
Cytochrome P-450 CYP3A / metabolism
Dose-Response Relationship, Drug
Drug Compounding / methods
Drug Development / methods
Female
Humans
Male
Middle Aged
Nonlinear Dynamics
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / pharmacokinetics*
Protein Kinase Inhibitors / therapeutic use

Substances

Aminopyridines
Antineoplastic Agents, Hormonal
Benzimidazoles
Protein Kinase Inhibitors
abemaciclib
Cytochrome P-450 CYP3A
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6