Sorafenib exposure decreases over time in patients with hepatocellular carcinoma.

BACKGROUND: Intra-patient variability in sorafenib pharmacokinetics has been poorly investigated to date. We hypothesized that sorafenib clearance could decrease over time, as seen with imatinib. PATIENTS AND METHODS: Sorafenib plasma concentrations were determined by liquid chromatography, every 2 weeks, in consecutive hepatocellular carcinoma patients treated with sorafenib. Sorafenib dose-normalized area under the concentration-time curve (AUC) was determined from a population pharmacokinetics model, and its kinetics was analyzed in order to identify possible alterations of exposure over time.
RESULTS: Fifteen hepatocellular carcinoma patients with Child-Pugh A cirrhosis, in whom sorafenib dosing remained unchanged from initiation of treatment to disease progression, were eligible for this analysis. Sorafenib AUC significantly decreased over time: the median AUC during the third month of treatment was lower than that observed after one month of treatment (43.0 vs. 60.3 mg/L.h, p = 0.008). Most importantly, median sorafenib AUC at the time of progression was almost two-fold lower than that observed after one month of therapy (33.2 vs. 60.3 mg/L.h, p = 0.007). These findings suggest an induction of expression of efflux transporters in the gut wall, or an induction of sorafenib metabolism.
CONCLUSIONS: In patients with progressive disease in whom exposure markedly decreased from baseline, sorafenib dose escalation could be considered, aiming to restore an adequate drug exposure and possibly anti-tumor activity.