Characterization of Neutropenia in Advanced Cancer Patients Following Palbociclib Treatment Using a Population Pharmacokinetic-Pharmacodynamic Modeling and Simulation Approach

• Published in: Journal of clinical pharmacology Vol. 57; no. 9; p. 1159
• Main Authors: Sun, Wan, O'Dwyer, Peter J, Finn, Richard S, Ruiz-Garcia, Ana, Shapiro, Geoffrey I, Schwartz, Gary K, DeMichele, Angela, Wang, Diane
• Format: Journal Article
• Language: English
• Published: England 01.09.2017
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Leukocyte Count; Male; Middle Aged; Models, Biological; Neoplasms - drug therapy; Neoplasms - metabolism; Neutropenia - chemically induced; Piperazines - administration & dosage; Piperazines - adverse effects; Piperazines - pharmacokinetics; Piperazines - therapeutic use; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - therapeutic use; Pyridines - administration & dosage; Pyridines - adverse effects; Pyridines - pharmacokinetics; Pyridines - therapeutic use; Young Adult; neutropenia; cancer; semimechanistic model; palbociclib; pharmacokinetic-pharmacodynamic model
• ISSN: 1552-4604
• DOI: 10.1002/jcph.902

Neutropenia is the most commonly reported hematologic toxicity following treatment with palbociclib, a cyclin-dependent kinase 4/6 inhibitor approved for metastatic breast cancer. Using data from 185 advanced cancer patients receiving palbociclib in 3 clinical trials, a pharmacokinetic-pharmacodynamic model was developed to describe the time course of absolute neutrophil count (ANC) and quantify the exposure-response relationship for neutropenia. These analyses help in understanding neutropenia associated with palbociclib and its comparison with chemotherapy-induced neutropenia. In the model, palbociclib plasma concentration was related to its antiproliferative effect on precursor cells through drug-related parameters (ie, maximum estimated drug effect and concentration corresponding to 50% of the maximum effect), and neutrophil physiology was mimicked through system-related parameters (ie, mean transit time, baseline ANC, and feedback parameter). Sex and baseline albumin level were significant covariates for baseline ANC. It was demonstrated by different model evaluation approaches (eg, prediction-corrected visual predictive check and standardized visual predictive check) that the final model adequately described longitudinal ANC with good predictive capability. The established model suggested that higher palbociclib exposure was associated with lower longitudinal neutrophil counts. The ANC nadir was reached approximately 21 days after palbociclib treatment initiation. Consistent with their mechanisms of action, neutropenia associated with palbociclib (cytostatic) was rapidly reversible and noncumulative, with a notably weaker antiproliferative effect on precursor cells relative to chemotherapies (cytotoxic). This pharmacokinetic-pharmacodynamic model aids in predicting neutropenia and optimizing dosing for future palbociclib trials with different dosing regimen combinations.