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.
Cynomolgus monkey recipients of life-supporting kidney allografts were treated orally with STN alone or in combination with cyclosporine A (CsA).
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.
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.
1Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
2Service de Chirurgie Générale et de Transplantation, Hôpital de Hautepierre, Strasbourg, France.
3Laboratoire d'Immunogénétique Moléculaire, EA 3034, Faculté de Médecine Purpan, Université Paul Sabatier, Toulouse 3, IFR150 INSERM, CHU de Toulouse, France.
This work was supported by Novartis Pharma AG, Basel, Switzerland.
M.B., G.W., C.B., C.H., R.E.M., and J.W. were employees of Novartis Pharma AG during the study. M.A. and A.B. have served as consultants for Novartis Pharma AG.
Address correspondence to: Marc Bigaud, Ph.D., Novartis Institutes for Biomedical Research (NIBR), Novartis Pharma AG, Novartis Campus, CH-4056 Basel, Switzerland. E-mail: email@example.com
M.B. was the scientific leader of the non-human primate transplantation program in NIBR and selected the donor/recipient pairs; G.W. performed necropsies and all histopathologic evaluations; C.B. performed analytics for drug blood levels; M.A. performed the surgical procedures; A.B. undertook the ABO and DRBexon2 typing; and C.H., R,E.M., and J.W. contributed to the study design and provided scientific support.
Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.transplantjournal.com).
Received 21 February 2011. Revision requested 9 March 2011.
Accepted 12 October 2011.