Population Pharmacokinetic-Pharmacodynamic Modelling of 24-h Diastolic Ambulatory Blood Pressure Changes Mediated by Axitinib in Patients with Metastatic Renal Cell Carcinoma

• Published in: Clinical pharmacokinetics Vol. 54; no. 4; pp. 397 - 407
• Main Authors: Chen, Ying, Rini, Brian I., Bair, Angel H., Mugundu, Ganesh M., Pithavala, Yazdi K.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.04.2015; Springer Nature B.V
• Subjects: Aged; Algorithms; Blood Pressure - drug effects; Blood Pressure Monitoring, Ambulatory - methods; Carcinoma, Renal Cell - blood; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - physiopathology; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Imidazoles - administration & dosage; Imidazoles - blood; Imidazoles - pharmacokinetics; Indazoles - administration & dosage; Indazoles - blood; Indazoles - pharmacokinetics; Internal Medicine; Kidney Neoplasms - blood; Kidney Neoplasms - drug therapy; Kidney Neoplasms - physiopathology; Linear Models; Male; Medicine; Medicine & Public Health; Middle Aged; Original Research Article; Pharmacology/Toxicology; Pharmacotherapy; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - blood; Protein Kinase Inhibitors - pharmacokinetics; Axitinib; Sunitinib; Ambulatory Blood Pressure Monitoring; Pazopanib; Akaike Information Criterion
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-014-0207-5

Background Increased blood pressure (BP) is commonly observed in patients treated with vascular endothelial growth factor pathway inhibitors, including axitinib. Ambulatory BP monitoring (ABPM) and pharmacokinetic data were collected in a randomised, double-blind phase II study of axitinib with or without dose titration in previously untreated patients with metastatic renal cell carcinoma. Objective Aims of these analyses were to (1) develop a population pharmacokinetic-pharmacodynamic model for describing the relationship between axitinib exposure and changes in diastolic BP (dBP) and (2) simulate changes in dBP with different axitinib dosing regimens. Methods We employed a three-stage modelling approach, which included development of (1) a baseline 24-h ABPM model, (2) a pharmacokinetic model from serial and sparse pharmacokinetic data, and (3) an indirect-response, maximum-effect ( E max ) model to evaluate the exposure-driven effect of axitinib on dBP. Simulations ( N  = 1,000) were performed using the final pharmacokinetic-pharmacodynamic model to evaluate dBP changes on days 4 and 15 of treatment with different axitinib doses. Results Baseline ABPM data from 62 patients were best described by 24-h mean dBP and two cosine terms. The final indirect-response E max model showed good agreement between observed 24-h ABPM data and population and individual predictions. The maximum increase in dBP was 20.8 %, and the axitinib concentration at which 50 % of the maximal increase in dBP was reached was 12.4 ng/mL. Conclusion Our model adequately describes the relationship between axitinib exposure and dBP increases. Results from these analyses may potentially be applied to infer dBP changes in patients administered axitinib at nonstandard doses.