Purpose Axitinib is an orally active multikinase inhibitor currently used to treat patients with metastatic renal cell carcinoma (RCC). This study examined the pharmacokinetics of axitinib and the relationship between peak drug concentration (C) and clinical outcomes in real-world practice. Methods Twenty patients with metastatic RCC treated with axitinib monotherapy were enrolled. Post-dose (1-4 h) blood samples were obtained, and axitinib C in plasma was measured by liquid chromatography-tandem mass spectrometry. Efficacy endpoints were best overall response (per RECIST 1.1) and progression-free survival (PFS). The safety endpoint was the cumulative incidence of dose-limiting toxicities (DLTs). Results Large inter- and intra-individual variability in dose-adjusted C was observed (0.02-11.2 ng/mL/mg). Axitinib absorption was significantly influenced by glucuronidation activity (P = 0.040). C at steady state was significantly higher in responders than in non-responders (P = 0.013). The optimal C cutoff to predict a clinical response was 12.4 ng/mL. The median PFS was significantly longer in patients who achieved an average steady state C above the threshold than in those who did not (799 vs. 336 days; P = 0.047). The cumulative incidence of DLTs was significantly higher in patients with C ≥ 40.2 ng/mL than in other patients (sub-hazard ratio, 4.13; 95% confidence interval, 1.27-13.5; P = 0.019). Conclusions The potential therapeutic window of axitinib C in metastatic RCC was estimated at 12.4-40.2 ng/mL. Pharmacokinetically guided dose titration using therapeutic drug monitoring may improve the efficacy and safety of axitinib, warranting further investigation in a larger patient population.
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