Pharmacokinetics of single-agent axitinib across multiple solid tumor types

• Published in: Cancer chemotherapy and pharmacology Vol. 74; no. 6; pp. 1279 - 1289
• Main Authors: Tortorici, Michael A., Cohen, Ezra E. W., Pithavala, Yazdi K., Garrett, May, Ruiz-Garcia, Ana, Kim, Sinil, Fruehauf, John P.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2014; Springer; Springer Nature B.V
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic agents; Area Under Curve; Biological and medical sciences; Biological Availability; Cancer Research; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Endocrinopathies; Female; Humans; Imidazoles - pharmacokinetics; Imidazoles - therapeutic use; Indazoles - pharmacokinetics; Indazoles - therapeutic use; Male; Malignant tumors; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Models, Biological; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Nonlinear Dynamics; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pneumology; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - therapeutic use; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Sex Factors; Thyroid. Thyroid axis (diseases); Tissue Distribution; Tumors; Tumors of the respiratory system and mediastinum; Young Adult; Population pharmacokinetics; Axitinib; Thyroid cancer; Non-small cell lung cancer; Melanoma; Endocrinopathy; Lung disease; Solid tumor; Tyrosine kinase inhibitor; Respiratory disease; Lung cancer; Thyroid diseases; Malignant tumor; non-small cell lung carcinoma; Indazole derivatives; Malignant melanoma; Bronchus disease; Cancer
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-014-2606-6

Purpose Axitinib, a potent and selective inhibitor of vascular endothelial growth factor receptors, showed antitumor activity as a single agent against several solid tumor types in Phase II and III trials. This study was conducted to evaluate axitinib pharmacokinetics across a variety of solid tumors. Methods The current study analyzed the pharmacokinetics of axitinib in 110 patients with non-small cell lung cancer (NSCLC), thyroid cancer, or melanoma from three Phase II trials plus 127 healthy volunteers, using nonlinear mixed-effects modeling. Boxplots of maximum observed plasma concentration ( C max ) and area under the plasma concentration–time curve (AUC) of data from these tumor populations was compared to C max and AUC from the final population pharmacokinetic model developed for metastatic renal cell carcinoma (mRCC) to compare axitinib pharmacokinetics across different tumor types. Results Axitinib disposition based on data from 237 subjects was best described using a two-compartment model with first-order absorption and lag time. Population estimates for systemic clearance, central volume of distribution, absorption rate constant, absolute bioavailability, and lag time were 20.1 L/h, 56.2 L, 1.26/h −1 , 0.663, and 0.448 h, respectively. Statistically significant covariates included gender on clearance, and body weight on central volume of distribution. However, predicted changes due to gender and body weight were found not clinically meaningful. The final analysis indicated that the pharmacokinetic model for mRCC was able to successfully describe axitinib pharmacokinetics in patients with NSCLC, thyroid cancer, and melanoma. Conclusion The pharmacokinetics of axitinib appears to be similar across a variety of tumor types.