title: Overview of sotrastaurin clinical pharmacokinetics.
abstract: Sotrastaurin (AEB071) is an investigational immunosuppressant that blocks T-lymphocyte activation through protein kinase C inhibition. It is currently in Phase II of clinical development for the prevention of acute rejection after solid organ transplantation. In renal transplant clinical trials, sotrastaurin has been administered at doses of 200 to 300 mg twice daily. Using a validated liquid chromatography method with tandem mass spectrometry, steady-state predose blood concentrations averaged approximately 600 and 900 ng/mL at these dose levels, respectively. Sotrastaurin is primarily metabolized through CYP3A4. There is one active metabolite, N-desmethyl-sotrastaurin, that is present at low blood concentrations (less than 5% of the parent exposure). The elimination half-life of sotrastaurin averages 6 hours. Clinical drug interaction studies to date have demonstrated that sotrastaurin increases the area under the concentration-time curve of everolimus 1.2-fold and of tacrolimus twofold. Conversely, sotrastaurin area under the concentration-time curve is increased up to 1.8-fold by cyclosporine and 4.6-fold by ketoconazole. Blood samples from renal transplant patients receiving sotrastaurin were stimulated ex vivo by protein kinase C-dependent pathways. Inhibition of cytokine production, expression of CD69, and thymidine uptake served as biomarkers that demonstrated the ability of sotrastaurin to inhibit T-cell activation and proliferation at the doses used in these studies. Phase II trials have paired sotrastaurin with tacrolimus, mycophenolic acid, or everolimus. The clinical and pharmacokinetic results of these and upcoming trials will determine the optimal immunosuppressive regimen to benefit from sotrastaurin's novel mechanism of action and whether therapeutic drug monitoring will be beneficial.
authors.affiliation: Novartis Pharmaceuticals, Basel, Switzerland. john.kovarik@novartis.com
authors.forename: John M
authors.initials: JM
authors.lastname: Kovarik
authors.forename: Alan
authors.initials: A
authors.lastname: Slade
mesh_terms: D015415:Biomarkers / Q000097:blood; D004347:Drug Interactions; D016903:Drug Monitoring; D006084:Graft Rejection / Q000188:drug therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects; D016377:Organ Transplantation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D015415:Biomarkers; D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; C543528:sotrastaurin; D011493:Protein Kinase C