Sotrastaurin, a protein kinase C inhibitor for the prevention of transplant rejection and treatment of psoriasis

Current Opinion in Investigational Drugs

Volumn 10, Issue 11, 2009, Pages 1225-1235

  Manicassamy, S ^a  

^a EMORY UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADALIMUMAB; ALEFACEPT; ALEMTUZUMAB; AZATHIOPRINE; BASILIXIMAB; CALCINEURIN INHIBITOR; CORTICOSTEROID; CYCLOSPORIN; EVEROLIMUS; FINGOLIMOD; KETOCONAZOLE; MYCOPHENOLIC ACID; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; OKT 3; PLACEBO; RAPAMYCIN; SOTRASTAURIN; TACROLIMUS;

ACNE; AREA UNDER THE CURVE; CATARACT; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; CONTACT DERMATITIS; DIARRHEA; DIZZINESS; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG CONTRAINDICATION; DRUG COST; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG MECHANISM; DRUG METABOLISM; DRUG POTENTIATION; DRUG SYNTHESIS; DRUG TOLERABILITY; DRUG WITHDRAWAL; DYSPEPSIA; GASTROINTESTINAL SYMPTOM; GRAFT REJECTION; GRAFT SURVIVAL; HEADACHE; HEART RATE; HUMAN; INFECTION; INFLAMMATION; KIDNEY GRAFT REJECTION; LIVER FUNCTION TEST; LIVER GRAFT REJECTION; LIVER TRANSPLANTATION; METABOLIC DISORDER; MONOTHERAPY; MYOPATHY; NAUSEA; NEPHROTOXICITY; NEUTROPENIA; NIGHT SWEAT; NONHUMAN; OBESITY; PATHOGENESIS; PSORIASIS; REVIEW; SIDE EFFECT; TIME TO MAXIMUM PLASMA CONCENTRATION; UVEITIS; VOMITING;

ANIMALS; CLINICAL TRIALS AS TOPIC; GRAFT REJECTION; HUMANS; ORGAN TRANSPLANTATION; PROTEIN KINASE C; PROTEIN KINASE INHIBITORS; PSORIASIS; PYRROLES; QUINAZOLINES;

EID: 70449371566     PISSN: 14724472     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (64)

1. Novel protein kinase C inhibitors for the prevention of allograft rejection: Synthesis, in vitro activity and pharmacokinetic data. Albert R, Beerli Ch, Cottens S, Evenou JP, Sedrani R, von Matt P, Wagner J, Weckbecker G, Zenke G AFMC INT MED CHEM SYMP 2003 5 Kyoto B-39
2. Asian Federation of Medicinal Chemistry (AFMC) - Fifth International Medicinal Chemistry Symposium (Part IV), Kyoto Japan, 14-17 October 2003. Hookes J IDDB MEETING REPORT 2003 October 14-17
3. Prevalence and treatment of psoriasis in the United Kingdom: A population-based study. Gelfand JM, Weinstein R, Porter SB, Neimann AL, Berlin JA, Margolis DJ ARCH DERMATOL 2005 141 12 1537-1541
4. NCT00403416: Effcacy and safety of AEB071 plus tacrolimus (converted to mycophenolic acid after 3 months), in renal transplant patients. Novartis AG CLINICALTRIALS.GOV 2006 November 22
5. NVP-AEB071 pharmacokinetics: Combination with mycophenolate mofetil (Cellcept) is safe and does not result in an interaction. Slade A, Pfrunder A, Koelle EU, Seiberling M, Schmouder R AM J TRANSPLANT 2006 6 Suppl 2 Abs 2436
6. NVP-AEB071 pharmacokinetics: Combination with everolimus does not result in clinically relevant interaction. Slade A, Bartlett M, van Marle S, Marbach P, Schmouder R AM J TRANSPLANT 2006 6 Suppl 2 Abs 2435
7. Pharmacokinetics (PK) of the novel oral protein kinase C (PKC) inhibitor NVP-AEB071(AEB) in rats and non-human primates (NHP): Study of immunosuppressive (IS) effcacy and distribution to lymphatic organs. Weckbecker G, Jean C, Pally C, Wagner J, Morris R, Bruns C, Bigaud M, Beerli C AM J TRANSPLANT 2006 6 Suppl 2 Abs 2114
8. First escalating single dose human volunteer study of the novel immunosuppressant (IS) NVP-AEB071 (AEB): Relationships among dose levels, PK and PD of immune functions. Burkhart C, Welzenbach K, Raulf F, Vitaliti A, Grenet O, Schmidli H, Belleli R, Marbach P, Wagener J, Morris RE, Rordorf C AM J TRANSPLANT 2006 6 Suppl 2 Abs 1897
9. Pharmacodynamics (PD) of T-cell inhibition by the new protein kinase C (PKC) inhibitor, NVP-AEB071 (AEB), in non-human primates (NHP). Bigaud M, Burkhart C, Raulf F, Vedrine C, Maurer C, Allard C, Preussing E, Cordoba F, Heusser C, Morris RE AM J TRANSPLANT 2006 6 Suppl 2 Abs 1896
10. NVP-AEB071 (AEB), a novel oral inhibitor of early T-cell activation, prolongs rat cardiac allograft survival when used alone and in combination with cyclosporine, everolimus or FTY720. Bruns CH, Pally C, Beerli C, Wieczorek G, Weckbecker G, Wagner J, Morris R AM J TRANSPLANT 2006 6 Suppl 2 Abs 741
11. NVP-AEB071 (AEB), the novel oral inhibitor of protein kinase C (PKC) and early T-cell activation, prolongs non-human primates (NHP) kidney allograft survival when combined with everolimus (RAD), ERL080 (ERL) or FTY720 (FTY) without calcineurin inhibitor (CNI). Bigaud M, Wieczorek G, Preussing E, Riesen S, Cordoba F, Audet M, Blancher A, Heusser C, Bruns C, Wagner J, Morris RE AM J TRANSPLANT 2006 6 Suppl 2 Abs 550
12. NVP-AEB071 (AEB), a novel oral inhibitor of early T-cell activation, prolongs the survival of non-human primate (NHP) kidney allografts when used as monotherapy or at non-effective doses combined with a non-effective dose of cyclosporine (CsA). Bigaud M, Wieczorek G, Riesen S, Menninger K, Barbet I, Jean C, Beerli C, Audet M, Blancher A, Heusser C, Wagner J et al AM J TRANSPLANT 2006 6 Suppl 2 Abs 546
13. NVP-AEB071: Human pharmacodynamics in combination with mycophenolic acid. Slade A, Vitaliti A, Agyemang A, Sieberling M, Schmouder R AM J TRANSPLANT 2006 6 Suppl 2 Abs 396
14. NVP-AEB071: Pharmacokinetics and pharmaco-dynamic activity of a novel T-cell activation inhibitor under multiple-dose conditions. Slade A, Hijazi Y, Wagner J, Vitaliti A, Stingl G, Griffths C, Jung T, Schmouder R AM J TRANSPLANT 2006 6 Suppl 2 Abs 392
15. NCT00572585: Effcacy, safety and tolerability of AEB071 in patients With active, moderate to severe ulcerative colitis. Novartis AG CLINICALTRIALS.GOV 2007
16. A 2-week multiple ascending dose, double-blind, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics, and effcacy of oral AEB071, a protein kinase C inhibitor, in moderate to severe psoriasis patients. Skvara H, Dawid M, Stingl G, Griffths C J AM ACAD DERMATOL 2008 58 Suppl 2 Abs P2600
17. NVP-AEB071 pharmacokinetics: Effect of metabolic inhibition with ketoconazole. Slade A, Kovarik JM, Huang A, Chandler P, Schmouder R AM J TRANSPLANT 2008 8 Suppl 2 Abs 1260
18. The PKC inhibitor AEB071 may be a therapeutic option for psoriasis. Skvara H, Dawid M, Kleyn E, Wolff B, Meingassner JG, Knight H, Dumortier T, Kopp T, Fallahi N, Stary G, Burkhart C et al J CLIN INVEST 2008 118 9 3151-3159
19. Protein kinase C inhibitor, AEB-071, acts complementarily with cyclosporine to prevent islet rejection in rats. Merani S, Pawlick RL, Edgar RL, Toso C, Emamaullee J, Anderson CC, Shapiro AMJ TRANSPLANTATION 2009 87 1 59-65
20. Novartis AG: Form 20-F for the year ended 31 December 2008. Novartis AG FORM 20-F 2009 January 28
21. AEB071, a novel protein kinase C-inhibitor: Evaluation of an AEB071 plus mycophenolate regimen in renal transplant recipients. Friman S, Arns W, Banas B, Chan L, Mulgaonkar S, Nashan B, Soergel M, Vincenti F, Wissing KM, Witte S, Woodle ES AM J TRANSPLANT 2009 9 Suppl 2 Abs 458
22. Pharmacokinetics and exposure-effcacy relationships of the protein kinase C inhibitor AEB071 in de novo kidney transplant patients. Kovarik JM, Steiger JU, Grinyo JM, Rostaing L, Arns W, Dantal J, Proot P, Barten MJ, Budde K AM J TRANSPLANT 2009 9 Suppl 2 Abs 751
23. Tacrolimus pharmacokinetics when combined with the protein kinase C inhibitor AEB071 in de novo kidney transplant patients. Kovarik JM, Steiger JU, Grinyo JM, Rostaing L, Arns W, Dantal J, Slade A, Barten MJ, Budde K AM J TRANSPLANT 2009 9 Suppl 2 Abs 457
24. AEB071, a novel protein kinase C-inhibitor: First clinical results of an AEB071 plus tacrolimus regimen in renal transplant recipients. Budde K, Sommerer C, Becker T, Asderakis A, Pietruck F, Grinyo JM, Rigotti P, Dantal J, Ng J, Barten MJ, Weber M AM J TRANSPLANT 2009 9 Suppl 2 Abs 391
25. AEB071 pharmacokinetics: Effect of hepatic impairment and consequent changes in serum protein concentrations. Slade A, Kovarik JM, Launonen A, Preston R, Schmouder R AM J TRANSPLANT 2009 9 Suppl 2 Abs 752
26. Pharmacokinetics of AEB071, a protein kinase C inhibitor, in de novo liver transplant recipients. Kovarik JM, Neuhaus P, Cillo U, Stitah S, Slade A AM J TRANSPLANT 2009 9 Suppl 2 Abs 1219
27. Effect of cyclosporine on AEB071 pharmacokinetics and lymphocyte pharmacodynamics. Slade A, Kovarik JM, Stitah S, Sfkas N, Vitaliti A, Seiberling M, Schmouder R AM J TRANSPLANT 2009 9 Suppl 2 Abs 747
28. AEB-071-treated immunodefcient mice exhibit better engraftment and function of transplanted human islets compared to sirolimus-treated controls. Merani S, Edgar RL, Pawlick RL, Davis J, McCall M, Toso C, Emamaullee JA, Kin T, Shapiro AMJ AM J TRANSPLANT 2009 9 Suppl 2 Abs 1702
29. Effects of the protein kinase C inhibitor AEB071 on human effector and regulatory T cells. de Weerd A, Kraaijeveld R, Quaedackers M, Weimar W, Baan C AM J TRANSPLANT 2009 9 Suppl 2 Abs 1704
30. AEB-071 has minimal impact on onset of autoimmune diabetes in NOD mice. Merani S, Edgar RL, Toso C, Emamaullee J, Thiesen A, Shapiro AMJ AUTOIMMUNITY 2009 42 3 242-248
31. What's next in the pipeline? Vincenti F, Kirk AD AM J TRANSPLANT 2008 8 10 1972-1981
32. A 2 week multiple ascending dose, double-blind placebo controlled study to evaluate the safety, tolerability, pharmacokinetics and effcacy of oral AEB071, a protein kinase C inhibitor, in moderate to severe psoriasis patients. Skvara H, Dawid M, Kopp T, Kleyn E, Knight H, Dumortier T, Hijazi Y, McGeown C, Marbach P, Griffths C, Stingl G et al J INVEST DERMATOL 2007 127 Suppl 1 Abs 256
33. NCT00545259: Pharmacokinetic study of AEB071 in patients following liver transplantation. Novartis AG CLINICALTRIALS. GOV 2007
34. Novartis delivers strong operational performance in H1 2009: Half year / second quarter 2009 results. Novartis AG COMPANY PRESENTATION 2009 July 16
35. The potent protein kinase C-selective inhibitor AEB071 (sotrastaurin) represents a new class of immunosuppressive agents affecting early T-cell activation. Evenou JP, Wagner J, Zenke G, Brinkmann V, Wagner K, Kovarik J, Welzenbach KA, Weitz-Schmidt G, Guntermann C, Towbin H, Cottens S et al J PHARMACOL EXP THER 2009 330 3 792-801
36. Blood PK and PD measurements of the novel protein kinase C inhibitor NVP-AEB071 (AEB) correlate with heart allograft survival times in rat. Burkhart C, Maassen J, Vogt G, Gasser R, Beerli C, Weckbecker G AM J TRANSPLANT 2007 7 Suppl 2 Abs 1090
37. NVP-AEB071: Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single doses from 10 to 1100 mg. Slade A, Marbach P, Burkhart C, Seiberling M, Schmouder R AM J TRANSPLANT 2007 7 Suppl 2 Abs 145
38. First escalating single dose human volunteer study of the novel immunosuppressant (IS) NVP-AEB071 (AEB): Relationships among dose levels, PK and PD of immune functions. Burkhart C, Welzenbach K, Raulf F, Vitaliti A, Grenet O, Schmidli H, Belleli R, Marbach P, Wagener J, Morris RE, Rordorf C TRANSPLANTATION 2006 82 1 698
39. NVP-AEB071: Pharmacokinetics and pharmaco-dynamic activity of a novel T-cell activation inhibitor under multiple-dose conditions. Slade A, Hijazi Y, Wagner J, Vitaliti A, Stingl G, Griffths C, Jung T, Schmouder R TRANSPLANTATION 2006 82 1 198
40. NVP-AEB071: Human pharmacodynamics in combination with mycophenolic acid. Slade A, Vitaliti A, Agyemang A, Sieberling M, Schmouder R TRANSPLANTATION 2006 82 1 199-200
41. NVP-AEB071 pharmacokinetics: Combination with everolimus does not result in clinically relevant interaction. Slade A, Bartlett M, van Marle S, Marbach P, Schmouder R TRANSPLANTATION 2006 82 1 865-866
42. NVP-AEB071 pharmacokinetics: Combination with mycophenolate mofetil (CellceptR) is safe and does not result in an interaction. Slade A, Pfrunder A, Koelle EU, Seiberling M, Schmouder R TRANSPLANTATION 2006 82 1 866
43. NVP-AEB071 pharmacokinetics: Effect of metabolic inhibition with ketoconazole. Slade A, Kovarik JM, Huang A, Chandler P, Schmouder R TRANSPLANTATION 2008 86 2 Suppl 411-412
44. NVP-AEB071 maximum tolerated dose: Safety and tolerability of a novel T-cell activation inhibitor. Slade A, Jung T, Dumortier T, Stingl G, Seiberling M, Wilmer J, Schmouder R TRANSPLANTATION 2008 86 2 Suppl 412
45. The IL-23/Th17 axis in the immunopathogenesis of psoriasis. Di Cesare A, Di Meglio P, Nestle FO J INVEST DERMATOL 2009 129 6 1339-1350
46. The role of serine/threonine kinases in T-cell activation. Matthews SA, Cantrell DA CURR OPIN IMMUNOL 2006 18 3 314-320
47. The life and death of protein kinase C. Gould CM, Newton AC CURR DRUG TARGETS 2008 9 8 614-625
48. Protein kinase C and beyond. Spitaler M, Cantrell DA NAT IMMUNOL 2004 5 8 785-790
49. Protein kinase C family functions in B-cell activation. Guo BC, Su TT, Rawlings DJ CURR OPIN IMMUNOL 2004 16 3 367-373
50. Protein kinase C S controls self-antigen-induced B-cell tolerance. Mecklenbrauker I, Saijo K, Zheng NY, Leitges M, Tarakhovsky A NATURE 2002 416 6883 860-865
51. Protein kinase C e (PKCe): A key player in T cell life and death. Hayashi K, Altman A PHARMACOL RES 2007 55 6 537-544
52. Selective modulation of protein kinase C-e during T-cell activation. Monks CRF, Kupfer H, Tamir I, Barlow A, Kupfer A NATURE 1997 385 6611 83-86
53. Selective function of PKC-e in T cells. Manicassamy S, Gupta S, Sun Z CELL MOL IMMUNOL 2006 3 4 263-270
54. PKC-e is required for TCR-induced NF-KB activation in mature but not immature T lymphocytes. Sun ZM, Arendt CW, Ellmeier W, Schaeffer EM, Sunshine MJ, Gandhi L, Annes J, Petrzilka D, Kupfer A, Schwartzberg PL, Littman DR NATURE 2000 404 6776 402-407
55. Immunodefciency in protein kinase C|-defcient mice. Leitges M, Schmedt C, Guinamard R, Davoust J, Schaal S, Stabel S, Tarakhovsky A SCIENCE 1996 273 5276 788-791
56. PKC inhibitors: Potential in T cell-dependent immune diseases. Baier G, Wagner J CURR OPIN CELL BIOL 2009 21 2 262-267
57. A critical role for protein kinase C- -mediated T cell survival in cardiac allograft rejection. Manicassamy S, Yin DP, Zhang Z, Molinero LL, Alegre ML, Sun ZM J IMMUNOL 2008 181 1 513-520
58. Defciency of protein kinase C-e facilitates tolerance induction. Wang L, Xiang ZD, Ma LL, Chen ZY, Gao XD, Sun ZM, Williams P, Chari RS, Yin DP TRANSPLANTATION 2009 87 4 507-516
59. Immunosuppressive drugs for kidney transplantation. Halloran PF N ENGL J MED 2004 351 26 2715-2729
60. Effcacy and safety of immunosuppressive drugs approved in EU through the centralised procedure. Bertele V, Buonocore C, Michelacci F, Vitocolonna M, Garattini S EUR J CLIN PHARMACOL 2007 63 7 707-712 (Pubitemid 46911336)
61. Mechanisms of disease: Psoriasis. Nestle FO, Kaplan DH, Barker J N ENGL J MED 2009 361 5 496-509
62. Novel immunosuppression: Small molecules and biologics. Yabu JM, Vincenti F SEMIN NEPHROL 2007 27 4 479-486
63. Psoriasis: Epidemiology. Gudjonsson JE, Elder JT CLIN DERMATOL 2007 25 6 535-546
64. Plasmacytoid dendritic cells in psoriasis. Bell E NAT REV IMMUNOL 2007 7 838-839