Sotrastaurin (AEB071) Alone and in Combination With Cyclosporine A Prolongs Survival Times of Non-Human Primate Recipients of Life-Supporting Kidney Allografts

作者：Bigaud Marc^*; Wieczorek Grazyna; Beerli Christian; Audet Maxime; Blancher Antoine; Heusser Christoph; Morris Randall E; Wagner Juergen

来源：Transplantation, 2012, 93(2): 156-164.

DOI：10.1097/TP.0b013e31823cf92f

• AEB071
• Immunosuppression
• Kidney
• Non-human primate
• Sotrastaurin
• Protein kinase C
• Transplant

Background. Sotrastaurin (STN), a novel oral protein kinase C inhibitor that inhibits early T-cell activation, was assessed in non-human primate recipients of life-supporting kidney allografts. %26lt;br%26gt;Methods. Cynomolgus monkey recipients of life-supporting kidney allografts were treated orally with STN alone or in combination with cyclosporine A (CsA). %26lt;br%26gt;Results. STN monotherapy at 50 mg/kg once daily prolonged recipient survival times to the predefined endpoint of 29 days (n=2); when given at 25 mg/kg twice daily, the median survival time (MST) was 27 days (n=4). Neither once-daily monotherapy of STN 20 mg/kg nor CsA 20 mg/kg was effective (MST 6 days [n=2] and 7 days [n=5], respectively). In combination, however, STN 20 mg/kg and CsA 20 mg/kg prolonged MST to more than 100 days (n=5). By combining lower once-daily doses of STN (7 or 2 mg/kg) with CsA (20 mg/kg), MST was more than 100 (n=3) and 22 days (n=2), respectively. Neither in single-dose pharmacokinetic studies nor the transplant recipients were STN or CsA blood levels for combined treatment greater than when either drug was administered alone. STN blood levels in transplant recipients during combination therapy were dose related (20 mg/kg, 30-182 ng/mL; 7 mg/kg, 7-41 ng/mL; and 2 mg/kg, 3-5 ng/mL). STN at a daily dose of up to 20 mg/kg was relatively well tolerated. %26lt;br%26gt;Conclusions. STN prolonged survival times of non-human primate kidney allograft recipients both as monotherapy and most effectively in combination with CsA. Pharmacokinetic interactions were not responsible for the potentiation of immunosuppressive efficacy by coadministering STN and CsA.

• 出版日期2012-1-27