Sorafenib - How It Works
Clinical pharmacology details from the US FDA-approved label: how Sorafenib works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
12.1 Mechanism of Action Sorafenib is a kinase inhibitor that decreases tumor cell proliferation in vitro.
Sorafenib was shown to inhibit multiple intracellular (c-CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT- 3, RET, RET/PTC, VEGFR-1, VEGFR- 2, VEGFR- 3, and PDGFR-ß).
Several of these kinases are thought to be involved in tumor cell signaling, angiogenesis and apoptosis.
Sorafenib inhibited tumor growth of HCC and DTC human tumor xenografts in immunocompromised mice.
Reductions in tumor angiogenesis were seen in models of HCC upon sorafenib treatment, and increases in tumor apoptosis were observed in models of HCC and DTC.
12.2 Pharmacodynamics Cardiac Electrophysiology The effect of sorafenib tablets 400 mg twice daily on the QTc interval was evaluated in a multi-center, open- label, non-randomized trial in 53 patients with advanced cancer.
No large changes in the mean QTc intervals (that is, >20 ms) from baseline were detected in the trial.
After one 28-day treatment cycle, the largest mean QTc interval change of 8.5 ms (upper bound of two-sided 90% confidence interval, 13.3 ms) was observed at 6 hours post-dose on day 1 of cycle 2 [see Warnings and Precautions , Drug Interactions ].
12.3 Pharmacokinetics Multiple doses of sorafenib tablets for 7 days resulted in a 2.5- to 7-fold accumulation compared to a single dose.
Steady-state plasma sorafenib concentrations were achieved within 7 days, with a peak-to-trough ratio of mean concentrations of less than 2.
The steady-state concentrations of sorafenib following administration of sorafenib tablets 400 mg twice daily were evaluated in DTC and HCC patients.
Patients with DTC have mean steady-state concentrations that are 1.8-fold higher than patients with HCC.
The reason for increased sorafenib concentrations in DTC patients is unknown.
Mean C max and AUC increased less than proportionally beyond oral doses of 400 mg administered twice daily.
Absorption After administration of sorafenib tablets, the mean relative bioavailability was 38–49% when compared to an oral solution.
Following oral administration, sorafenib reached peak plasma levels in approximately 3 hours.
Effects of Food With a moderate-fat meal (30% fat; 700 calories), bioavailability was similar to that in the fasted state.
With a high-fat meal (50% fat; 900 calories), bioavailability was reduced by 29% compared to that in the fasted state.
Distribution In vitro binding of sorafenib to human plasma proteins was 99.5%.
Elimination The mean elimination half-life of sorafenib was approximately 25 to 48 hours.