Sorafenib is an orally administered multikinase inhibitor that exhibits antiangiogenic and antitumor activity. Few investigators have been able to correlate cumulative
sorafenib dose or total exposure to pharmacodynamic effects. This discrepancy may be in part due to poorly understood protein binding characteristics. Since unbound
drug concentrations are believed to be more relevant to pharmacological and toxicological responses than total
drug, an equilibrium dialysis method using 96-well microdialysis plates was optimized and validated for determining the fraction unbound (F(u))
sorafenib in human plasma and in isolated
protein solutions. Unbound
sorafenib concentrations were determined in
cancer patients receiving the
drug orally at a dose of 400 mg and 600 mg twice daily.
Sorafenib was extensively bound with mean F(u) value of 0.3% in both non-
cancer and
cancer patient's plasma. The binding in plasma was concentration independent, indicating a low-affinity, possibly nonspecific and nonsaturable process. In isolated
protein solutions, 99.8% and 79.3% of
sorafenib was bound to
human serum albumin (HSA) (4 g/dL) and α(1)-acid
glycoprotein (AAG) (0.1 g/dL) with binding constants of 1.24 × 10(6) M(-1) and 1.40 × 10(5) M(-1), respectively. In
cancer patients receiving
sorafenib, unbound
sorafenib was not correlated with patient characteristics or laboratory values. In conclusion,
sorafenib is highly
protein bound in human plasma with a higher affinity towards
albumin and limited free
drug may be partly responsible for its borderline clinical activity.