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

Privileged Structures - Dream or Reality: Preferential Organization of Azanaphthalene Scaffold

“…Sotrastaurin (AEB071) is a potent inhibitor protein kinase C (PKC) that attenuates the activation of lymphocyte T immunoactive cells [265,266]. The drug is now under phase II trials for its safety, tolerability and pharmacokinetics in two large studies focused on renal and liver transplantations [267][268][269]. Another example of quinazoline inhibitors of protein kinases is cediranib (Recentin), which is a derivative of known anticancer inhibitors of kinases such as gefitinib or lapatinib [217,270].…”

Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

“…Sotrastaurin (AEB071), another potent PKC inhibitor (Ki 0.2–3.2 nM), shows some specificity for PKC θ , PKC α , and PKC β compared to PKC δ , PKC ε , and PKC η (Evenou et al, 2009), but it also shows a significant inhibition of many other kinases. Sotrastaurin inhibits T-cell activation by peptide–MHC and CD28 co-stimulation in a PKC-dependent manner (Evenou et al, 2009; Wagner et al, 2009) and is currently in clinical trials for liver transplantation (Matz et al, 2011) and renal transplantation (Kovarik et al, 2011). …”

Protein Kinase C-Dependent Signaling Controls the Midgut Epithelial Barrier to Malaria Parasite Infection in Anopheline Mosquitoes

“…Mammalian PKCs have also been implicated in the regulation of malaria parasite egress from RBCs and treatment of P. berghei- infected mice with the PKC inhibitor sotrastaurin [71], [72] significantly decreased parasitemia and increased survival of infected hosts [73]. Given that circulating levels of sotrastaurin in blood can range from ∼0.1–2.3 µM following a single treatment [74], parasites that ‘escape’ this targeted drug treatment in the human host would be ingested along with the inhibitor by mosquitoes that feed on these treated hosts. Ingested PKC inhibitor – as indicated by our data – can block parasite development in the mosquito host, providing a second level of control under natural conditions for transmission.…”