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21-05-2013 | Article

Axitinib pharmacokinetics may guide dosing

Abstract

Free abstract

medwireNews: Research has shed light on the optimal use of the selective vascular endothelial growth factor receptor inhibitor axitinib for patients with metastatic renal cell carcinoma (mRCC).

Analysis of pooled data for 17 trials, including 383 healthy volunteers, 181 patients with mRCC and 26 patients with other solid tumors, suggests that both progression-free and overall survival are significantly associated with higher drug exposure and increasing diastolic blood pressure (dBP).

"These findings support axitinib dose titration to increase plasma exposure in patients who tolerate axitinib, and also demonstrate [dBP] as a potential marker of efficacy," write Brian Rini (Cleveland Clinic Taussig Cancer Institute, Ohio, USA) and co-authors.

The team calculated the estimated mean systemic clearance (CL) to be 14.6 L/h and the central volume of distribution (Vc) to be 47.3 L within a linear 2-compartment model.

After adjusting for 12 confounding factors within the pharmacokinetic model, the team found that CL was significantly slower in participants aged over 60 years compared with younger individuals, Japanese participants compared with those of other ethnicities, and nonsmokers versus smokers, while Vc rose significantly with body weight.

However, the magnitude of change predicted by these factors were not large enough to warrant dose adjustment, Rini et al say.

By contrast, multivariate efficacy analysis showed that both progression-free and overall survival were significantly influenced by receipt of prior therapy (hazard ratio [HR]=1.6 and 2.1, respectively), Eastern cooperative Oncology Group Performance status (0 vs 1, HR=1.8 and 2.4), hemoglobin level (≤13 vs >13 mg/dL for men, ≤11.5 vs >11.5 mg/dL for women, HR=0.6 and 0.3), area under the curve (axitinib AUC per 100 h x ng/mL increase, HR=0.9 and 0.9), and dBP (per 10 mmHg increase, HR=0.7 and 0.7).

"It is unlikely that sustained increase in BP is required for efficacy; rather the transient increase in BP generally seen soon after initiation of treatment, which is subsequently managed with treatment, may be the predictor of efficacy," the researchers say.

"Early detection through close monitoring of dBP, and strict control of axitinib-related increase in dBP when it occurs, are critical for maintaining patients on treatment with axitinib to improve clinical outcomes."

The team adds: "The observed variability in axitinib [pharmacokinetics] suggests some patients achieve only sub-therapeutic plasma concentrations at the starting dose of 5 mg bid. In these patients, dose increases above 5 mg bid may be justified to increase plasma exposures, which in turn would lead to improved clinical benefits, as long as patients tolerate the drug."

medwireNews (www.medwirenews.com) is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2013

By Lynda Williams, Senior medwireNews Reporter