Axitinib in Metastatic Renal Cell Carcinoma: Results of a Pharmacokinetic and Pharmacodynamic Analysis

Abstract

Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, approved for second-line therapy for advanced renal cell carcinoma (RCC). Axitinib population pharmacokinetic and pharmacokinetic/pharmacodynamic relationships were evaluated. Using nonlinear mixed effects modeling with pooled data from 383 healthy volunteers, 181 patients with metastatic RCC, and 26 patients with other solid tumors in 17 trials, the disposition of axitinib was best described by a 2-compartment model with first-order absorption and a lag time, with estimated mean systemic clearance (CL) of 14.6 L/h and central volume of distribution (Vc) of 47.3 L. Of 12 covariates tested, age over 60 years and Japanese ethnicity were associated with decreased CL, whereas Vc increased with body weight. However, the magnitude of predicted changes in exposure based on these covariates does not warrant dose adjustments. Multivariate Cox proportional hazard regression and logistic regression analyses showed that higher exposure and diastolic blood pressure were independently associated with longer progression-free and overall survivals and higher probability of partial response in metastatic RCC patients. These findings support axitinib dose titration to increase plasma exposure in patients who tolerate axitinib, and also demonstrate diastolic blood pressure as a potential marker of efficacy.

Can individualized sunitinib dose and schedule changes optimize outcomes for kidney cancer patients?

“…As is the case for sunitinib, an association between higher AUC and better outcome has been documented for pazopanib 25 and axitinib 26 and dose escalation may improve the activity of sorafenib. [27][28][29] Traditionally, these three drugs are given continuously without a break, with dose reductions if toxicity is encountered on continuous therapy.…”

Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

“…Diastolic blood pressure (dBP) ≥90 mmHg has been associated with increased probability of response, PFS, and OS in RCC patients 41, 42. Based on these results, a randomized phase II trial to individualize axitinib dose based on dBP has been performed 43.…”

“…The available data support using an AUC ≥300 ng*h/mL as a target for TDM 42. However, given that prospective studies using dBP are already available, an integrated approach using both PK and dBP to guide dosing may be the most appropriate strategy to optimize treatment, as has been advocated previously 46.…”

Pharmacokinetic‐Guided Dosing of New Oral Cancer Agents

“…74 Other work has demonstrated an exposure-response relationship, with a clear relationship now being established between AUC and survival. [75][76][77] In addition to AUC, change in diastolic blood pressure (DBP) has become an established pharmacodynamic surrogate for axitinib efficacy. [77][78][79][80] Although DBP may show considerable intrapatient variability, the possibility of dose titration based on exposure has not been confirmed, and hence until PK targets are identified, dosing based on DBP is probably a better axitinib dose-individualization strategy than TDM, at least in renal cell cancer patients.…”