Effects of the novel protein kinase C inhibitor AEB071 (Sotrastaurin) on rat cardiac allograft survival using single agent treatment or combination therapy with cyclosporine, everolimus or FTY720.
NVP-AEB071 (AEB, sotrastaurin), an oral inhibitor of protein kinase C (PKC), effectively blocks T-cell activation. The immunosuppressive effects of oral AEB were demonstrated in a rat local graft versus host (GvH) reaction and rat cardiac transplantation models. T-cell activation was suppressed by 95% in blood from AEB-treated rats, with a positive correlation between T-cell inhibition and AEB blood concentration. In GvH studies, AEB inhibited lymph node swelling dose-dependently (3-30 mg/kg). BN and DA cardiac allografts were acutely rejected within 6-10 days post-transplantation in untreated LEW rats. AEB at 10 and 30 mg/kg b.i.d. prolonged BN graft survival to a mean survival time of 15 and >28 days, and DA grafts to 6.5 and 17.5 days, respectively. In the DA to LEW model, combining a nonefficacious dose of AEB (10 mg/kg b.i.d.) with a nonefficacious dose of cyclosporine, everolimus or FTY720 led to prolonged median survival times (26 days, >68 days and >68 days, respectively). Pharmacokinetic monitoring excluded drug-drug interactions, suggesting synergy. In conclusion, these studies are the first to demonstrate that AEB prolongs rat heart allograft survival safely as monotherapy and in combination with nonefficacious doses of cyclosporine, everolimus or FTY720. Thus, AEB may have the potential to offer an alternative to calcineurin inhibitor-based therapies.
Weckbecker
Gisbert
G
Novartis Institutes for BioMedical Research, Autoimmunity and Transplantation Disease Area, Novartis Pharma AG, Basel, Switzerland. gisbert.weckbecker@novartis.com
Pally
Charles
C
Beerli
Christian
C
Burkhart
Christoph
C
Wieczorek
Grazyna
G
Metzler
Barbara
B
Morris
Randall E
RE
Wagner
Juergen
J
Bruns
Christian
C
D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage*; D004347:Drug Interactions; D004359:Drug Therapy, Combination / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000068338:Everolimus; D000068876:Fingolimod Hydrochloride; D016027:Heart Transplantation / Q000379:methods*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008297:Male; D011409:Propylene Glycols / Q000008:administration & dosage*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives*
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D011758:Pyrroles; D011799:Quinazolines; C543528:sotrastaurin; D016572:Cyclosporine; D000068338:Everolimus; D011493:Protein Kinase C; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D020123:Sirolimus