, Volume 42, Issue 2, pp 366–374 | Cite as

Multiple once-daily subcutaneous doses of pasireotide were well tolerated in healthy male volunteers: a randomized, double-blind, placebo-controlled, cross-over, Phase I study

  • Christoph Beglinger
  • Ke Hu
  • Ying Wang
  • Emmanuel Bouillaud
  • Christelle Darstein
  • Yanfeng Wang
  • Pharis Mohideen
Original Article


A randomized, double-blind, placebo-controlled, cross-over, dose-escalating, single-center study was conducted to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of multiple once-daily (qd) subcutaneous (sc) doses of pasireotide in healthy male subjects. Subjects received pasireotide 50, 200, or 600 μg sc qd for 14 days and placebo in separate sequences. Thirty-three subjects were randomized. The most frequently reported drug-related adverse events were injection–site reactions (n = 18), diarrhea (n = 14) and nausea (n = 10), which were mostly mild or moderate in intensity. Pasireotide 600 μg sc was associated with pre- and post-prandial elevations in glucose levels relative to placebo; however, this effect was less pronounced on day 14 compared with day 1. PK steady state appeared to be achieved after 3 days of dosing and PK exposures had a moderate accumulation of 20–40 % across doses. Pasireotide demonstrated fast absorption (Tmax,ss: 0.25–0.5 h), low clearance (CL/Fss: 8.10–9.03 L/h), long effective half-life (T½,eff: ~12 h, on average between 9.7 and 13.1 h for 50, 200, and 600 μg sc qd), and large volume of distribution (Vz/Fss: 251–1,091 L) at steady state. Dose proportionality was confirmed for Cmax,ss; other PK parameters (Cmax, AUC0–24 h and AUCtau) were approximately dose proportional. Growth hormone inhibition was observed with pasireotide 200 and 600 μg sc qd. Gallbladder volume increased post-prandially with pasireotide 200 and 600 μg sc qd, which appeared to correlate with reduced levels of cholecystokinin at these doses. Pasireotide was generally well tolerated up to the tested dose of 600 μg qd, with a linear and time-independent PK profile after sc qd dosing in healthy subjects.


Pasireotide Safety Tolerability Pharmacokinetics Healthy volunteers 


  1. 1.
    U. Kumar, Cross-talk and modulation of signaling between somatostatin and growth factor receptors. Endocrine 40, 168–180 (2011)PubMedCrossRefGoogle Scholar
  2. 2.
    A. Ben-Shlomo, H. Schmid, K. Wawrowsky et al., Differential ligand-mediated pituitary somatostatin receptor subtype signaling: implications for corticotroph tumor therapy. J. Clin. Endocrinol. Metab. 94, 4342–4350 (2009)PubMedCrossRefGoogle Scholar
  3. 3.
    C. Bruns, I. Lewis, U. Briner, G. Meno-Tetang, G. Weckbecker, SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur. J. Endocrinol. 146, 707–716 (2002)PubMedCrossRefGoogle Scholar
  4. 4.
    H.A. Schmid, Pasireotide (SOM230): development, mechanism of action and potential applications. Mol. Cell. Endocrinol. 286, 69–74 (2008)PubMedCrossRefGoogle Scholar
  5. 5.
    J. Van Der Hoek, W.W. de Herder, R.A. Feelders et al., A single-dose comparison of the acute effects between the new somatostatin analog SOM230 and octreotide in acromegalic patients. J. Clin. Endocrinol. Metab. 89, 638–645 (2004)PubMedCrossRefGoogle Scholar
  6. 6.
    I. Donangelo, S. Melmed, Treatment of acromegaly: future. Endocrine 28, 123–128 (2005)PubMedCrossRefGoogle Scholar
  7. 7.
    L. Kvols, J.E. Glusman, E.A. Hahn et al., The effects of pasireotide (SOM230) on health-related quality of life in patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR. J. Clin. Oncol. 25(18S), abst 4558 (2007)Google Scholar
  8. 8.
    L. Kvols, B. Wiedenmann, K. Oberg et al., Safety and efficacy of pasireotide (SOM230) in patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR: results of a Phase II study. ASCO Gastrointestinal Cancers Symposium, San Francisco, 26–28 January 2006, abst 171Google Scholar
  9. 9.
    K.I. Alexandraki, G. Kaltsas, Gastroenteropancreatic neuroendocrine tumors: new insights in the diagnosis and therapy. Endocrine 41, 40–52 (2012)PubMedCrossRefGoogle Scholar
  10. 10.
    L.J. Hofland, S.W. Lamberts, The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocr. Rev. 24, 28–47 (2003)PubMedCrossRefGoogle Scholar
  11. 11.
    L.J. Hofland, J. Van Der Hoek, R. Feelders et al., The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5. Eur. J. Endocrinol. 152, 645–654 (2005)PubMedCrossRefGoogle Scholar
  12. 12.
    D.L. Batista, X. Zhang, R. Gejman et al., The effects of SOM230 on cell proliferation and adrenocorticotropin secretion in human corticotroph pituitary adenomas. J. Clin. Endocrinol. Metab. 91, 4482–4488 (2006)PubMedCrossRefGoogle Scholar
  13. 13.
    Y. Horsmans, K. Hu, M. Ruffin et al., Effect of hepatic impairment on the pharmacokinetics of pasireotide (SOM230): results from a multicenter Phase I study. J. Clin. Pharmacol. 52, 552–558 (2012)PubMedCrossRefGoogle Scholar
  14. 14.
    P. Ma, Y. Wang, J. Van Der Hoek et al., Pharmacokinetic-pharmacodynamic comparison of a novel multiligand somatostatin analog, SOM230, with octreotide in patients with acromegaly. Clin. Pharmacol. Ther. 78, 69–80 (2005)PubMedCrossRefGoogle Scholar
  15. 15.
    S. Petersenn, N. Unger, K. Hu et al., Pasireotide (SOM230), a novel multi-receptor-targeted somatostatin analogue, is well tolerated when administered as a continuous 7-day subcutaneous infusion in healthy male volunteers. J. Clin. Pharmacol. doi:10.1177/0091270011408727, [Epub ahead of print] (2011)
  16. 16.
    S. Petersenn, K. Hu, M. Maldonado et al., Tolerability and dose-proportional pharmacokinetics of pasireotide administered as a single dose or two divided doses in healthy male volunteers: a single-center, open-label, ascending-dose study. Clin. Ther. 34, 677–688 (2012)PubMedCrossRefGoogle Scholar
  17. 17.
    M. Shenouda, M. Maldonado, Y. Wang et al., An open-label, dose-escalation study of once- and twice-daily pasireotide in healthy volunteers: safety, tolerability and effects on glucose, insulin and glucagon levels. Am. J. Ther. (2012 in press)Google Scholar
  18. 18.
    M. Boscaro, W.H. Ludlam, B. Atkinson et al., Treatment of pituitary dependent Cushing’s disease with the multi-receptor ligand somatostatin analog pasireotide (SOM230): a multicenter, Phase II trial. J. Clin. Endocrinol. Metab. 94, 115–122 (2009)PubMedCrossRefGoogle Scholar
  19. 19.
    M. Boscaro, Y. Zhang, K. Sen et al., Long-term treatment of Cushing’s disease with pasireotide (SOM230): results from a Phase II extension study. Endocr. Rev. 31(3 Suppl 1), S333, abst P1-274 (2010)Google Scholar
  20. 20.
    M. Bronstein, F. Gu, C.-C. Shen et al. A randomized, blinded, multicenter, Phase III study to assess the efficacy and safety of pasireotide LAR versus octreotide LAR in patients with active acromegaly. 14th European NeuroEndocrine Association Congress, Liege, 22–25 September 2010, abst OC-6.1Google Scholar
  21. 21.
    A. Colao, J. Fleck, S. Pain et al., Pasireotide LAR versus octreotide LAR or lanreotide autogel in patients with inadequately controlled acromegaly: a Phase III, multicenter, randomized, parallel-group study. 14th European Neuroendocrine Association Congress, Liege, 22–25 September 2010, abst OC-6.2Google Scholar
  22. 22.
    A. Colao, S. Petersenn, J. Newell-Price et al., A 12-month Phase 3 study of pasireotide in Cushing’s disease. N. Engl. J. Med. 366, 914–924 (2012)PubMedCrossRefGoogle Scholar
  23. 23.
    L. Kvols, K. Oberg, T.M. O’Dorisio et al., Efficacy, safety and pharmacokinetic results from a Phase II study of pasireotide (SOM230) in the treatment of patients with metastatic NETs refractory or resistant to octreotide LAR. Neuroendocrinology 92(1), abst C57 (2010)Google Scholar
  24. 24.
    S. Petersenn, J. Schopohl, A. Barkan et al., Pasireotide (SOM230) demonstrates efficacy and safety in patients with acromegaly: a randomized, multicenter, Phase II trial. J. Clin. Endocrinol. Metab. 95, 2781–2789 (2010)PubMedCrossRefGoogle Scholar
  25. 25.
    H. Dietrich, K. Hu, M. Ruffin et al., Safety, tolerability and pharmacokinetics of a single dose of pasireotide long-acting release (LAR) in healthy volunteers: a single-center Phase I study. Eur. J. Endocrinol. doi:10.1530/EJE-11-0773, [Epub ahead of print] (2012)
  26. 26.
    Metropolitan Life Insurance Company, Metropolitan height and weight tables. Stat. Bull. 64, 2–9 (1983)Google Scholar
  27. 27.
    H. Boxenbaum, M. Battle, Effective half-life in clinical pharmacology. J. Clin. Pharmacol. 35, 763–766 (1995)PubMedGoogle Scholar
  28. 28.
    B.P. Smith, F.R. Vandenhende, K.A. DeSante et al., Confidence interval criteria for assessment of dose proportionality. Pharm. Res. 17, 1278–1283 (2000)PubMedCrossRefGoogle Scholar
  29. 29.
    J. Hasskarl, M. Kaufmann, H.A. Schmid, Somatostatin receptors in non-neuroendocrine malignancies: the potential role of somatostatin analogs in solid tumors. Future Oncol. 7, 895–913 (2011)PubMedCrossRefGoogle Scholar
  30. 30.
    G. Mazziotti, C. Gazzaruso, A. Giustina, Diabetes in Cushing syndrome: basic and clinical aspects. Trends Endocrinol. Metab. 22, 499–506 (2011)PubMedCrossRefGoogle Scholar
  31. 31.
    R.R. Henry, S. Mudaliar, K. Wetli-Hermosillo et al., Mechanism and management of hyperglycemia associated with pasireotide: results from studies in healthy volunteers. Endocr. Rev. 32(03), abst P3-274 (2011)Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Christoph Beglinger
    • 1
    • 4
  • Ke Hu
    • 2
  • Ying Wang
    • 2
  • Emmanuel Bouillaud
    • 3
  • Christelle Darstein
    • 3
  • Yanfeng Wang
    • 2
  • Pharis Mohideen
    • 2
  1. 1.Division of GastroenterologyUniversity Hospital BaselBaselSwitzerland
  2. 2.Novartis PharmaceuticalsEast HanoverUSA
  3. 3.Novartis Pharma AGBaselSwitzerland
  4. 4.Department of BiomedicineUniversity Hospital BaselBaselSwitzerland

Personalised recommendations