Development and Application of a Mechanistic Population Modeling Approach to Describe Abemaciclib Pharmacokinetics
| Autor: | Jan-Stefan van der Walt, Emmanuel Chigutsa, Siva Rama Prasad Kambhampati, P. Kellie Turner, Amanda K. Sykes, Maria M. Posada |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
Male Antineoplastic Agents Hormonal Drug Compounding Population Aminopyridines Breast Neoplasms Pharmacology Article chemistry.chemical_compound Breast cancer Drug Development Pharmacokinetics Cyclin-dependent kinase Antineoplastic Combined Chemotherapy Protocols Cytochrome P-450 CYP3A Humans Medicine Pharmacology (medical) education Protein Kinase Inhibitors Abemaciclib Active metabolite Aged Aged 80 and over education.field_of_study Dose-Response Relationship Drug biology business.industry Research lcsh:RM1-950 Healthy subjects Cyclin-Dependent Kinase 4 Cancer Cyclin-Dependent Kinase 6 Articles Middle Aged medicine.disease lcsh:Therapeutics. Pharmacology Nonlinear Dynamics chemistry Case-Control Studies Modeling and Simulation biology.protein Benzimidazoles Female business |
| Zdroj: | CPT: Pharmacometrics & Systems Pharmacology CPT: Pharmacometrics & Systems Pharmacology, Vol 9, Iss 9, Pp 523-533 (2020) |
| ISSN: | 2163-8306 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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