Sotrastaurin single-dose pharmacokinetics in de novo liver transplant recipients

Abstract: P>Sotrastaurin is a protein kinase C inhibitor in development for prevention of rejection after liver transplantation. In a pharmacokinetic study, 13 de novo liver transplant recipients received 100 mg sotrastaurin once between days 1-3 and once between days 5-8 post-transplant. Sotrastaurin absorption based on the area under the concentration-time curve (AUC) of total drug in blood (3544 +/- 1434 ng center dot h/ml) was similar to that of healthy subjects in a previous study (4531 +/- 1650 ng center dot h/ml). However, the sotrastaurin binding protein, alpha 1-acid glycoprotein, was nominally higher in patients (1.07 +/- 0.28 vs. 0.87 +/- 0.16 g/l, P = 0.13) yielding a 60% lower AUC based on free drug versus that in healthy subjects (27 +/- 13 vs. 62 +/- 15 ng center dot h/ml, P < 0.0001). There was minor excretion of sotrastaurin in drained bile (1% of dose) consistent with the fact that sotrastaurin is extensively metabolized leaving little unchanged drug to excrete. In the first week after liver transplantation, sotrastaurin is bioavailable after oral administration. However, patients with elevated alpha 1-acid glycoprotein levels may have lower free drug concentrations. Whether a higher dose of sotrastaurin is needed to compensate for this in the short-term after surgery will be addressed in future clinical trials.