Department of Internal Medicine, Erasmus MC, Sector of Endocrinology, Rotterdam, The Netherlands
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RefeRenceS 165
postinfusion rebound hypersecretion of hormones considerably hampered the initial enthusiasm, as well as its clinical use [5].
Octreotide acetate (Sandostatin®, SMS 201-995) was the first octapeptide somato-statin analogue that was synthesized. Its elimination half-life after subcutaneous administration is two hours, and rebound hypersecretion of hormones does not occur [6]. Somatostatin and its commercially available analogues octreotide and lanreotide (Somatuline®, BIM 23014) exert their effects through interaction with somatostatin receptor, which are expressed on the cells. Somatostatin binds with high affinity to all somatostatin subtypes 1 through 5 (sst1–5), whereas octreotide and lanreotide bind only with a high affinity to sst2 and sst5 [5, 7]. expression of somatostatin receptors by endocrine tumors is essential for the control of hormonal hypersecretion by the octapeptide somatostatin analogues. In sst2- or sst5-positive patients, clinical symp-tomatology related to hormonal hypersecretion can be controlled by the chronic administration of one of the currently available octapeptide somatostatin analogues [5, 8–11]. These drugs may also exert antiproliferative actions in these patients [9, 12–15].
referenceS
[1] Reichlin, S. new england Journal of Medicine 1983, 309, 1556–1563.
[2] Reichlin, S. new england Journal of Medicine 1983, 309, 1495–1501.
[3] Krulich, L.; Dhariwal, A. P.; Mccann, S. M. endocrinology 1968, 83, 783–790.
[4] Brazeau, P.; Vale, W.; Burgus, R.; et al. Science 1973, 179, 77–79.
[5] Lamberts, S. W.; van der Lely, A. J.; de Herder, W. W.; Hofland, L. J. new england Journal of Medicine 1996, 334, 246–254.
[6] Bauer, W.; Briner, U.; Doepfner, W.; et al. Life Sciences 1982, 31, 1133–1140.
[7] Patel, Y. c. frontiers in neuroendocrinology 1999, 20, 157–198.
[8] Kvols, L. K.; Moertel, c. G.; O’connell, M. J.; Schutt, A. J.; Rubin, J.; Hahn, R. G.
new england Journal of Medicine 1986, 315, 663–666.
[9] colao, A.; cappabianca, P.; caron, P.; et al. clinical endocrinology (Oxford) 2009, 70, 757–768.
[10] feelders, R. A.; Hofland, L. J.; van Aken, M. O.; et al. Drugs 2009, 69, 2207–2226.
[11] Oberg, K.; Kvols, L.; caplin, M.; et al. Annals of Oncology 2004, 15, 966–973.
[12] Shojamanesh, H.; Gibril, f.; Louie, A.; et al. cancer 2002, 94, 331–343.
[13] Rinke, A.; Muller, H. H.; Schade-Brittinger, c.; et al. Journal of clinical Oncology 2009, 27, 4656–4663.
[14] colao, A.; Pivonello, R.; Auriemma, R. S.; et al. Journal of clinical endocrinology and Metabolism 2008, 93, 3436–3442.
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Somatostatin Analogues: From Research to Clinical Practice, First Edition. Edited by Alicja Hubalewska-Dydejczyk, Alberto Signore, Marion de Jong, Rudi A. Dierckx, John Buscombe, and Christophe Van de Wiele.
© 2015 John Wiley & Sons, Inc. Published 2015 by John Wiley & Sons, Inc.
In the early 1980s, several somatostatin analogues were developed including SMS 201‐995 (octreotide acetate, Sandostatin®; Novartis, Basel, Switzerland), RC‐160 (Vapreotide, Sanvar®, Octastatin), BIM‐23014 (lanreotide, Somatuline®; Ipsen, Paris, France), and MK 678 (Seglitide). These new drugs are more resistant to biological degradation in the body than native somatostatin [1, 2]. As a result, their half‐lives and biological activities are considerably longer than that of native somatostatin (1.5–2 h vs. 1–2 min). At present, only octreotide and lanreotide are still clinically used.
While native somatostatin binds with high affinity to all somatostatin receptor subtypes (sst1–5), octreotide and lanreotide only bind with a high affinity to sst2 and sst5 (Table 5.1.1) [3]. Octreotide acetate (Sandostatin®) was the first octapeptide somatostatin analogue developed for clinical use [4]. Another advantage of this drug over native somatostatin is that rebound hypersecretion of hormones does not occur [4]. Octreotide has to be administered two to three times daily as a subcutaneous for-mulation (in single doses ranging from 100 to 500 µg) or can be administered as a continuous intravenous infusion [5]. The development of an intramuscular depot for-mulation of octreotide, Sandostatin® long‐acting repeatable (LAR®) (Novartis, Basel, Switzerland), which can be administered up to 30–90 mg once every 3–4 weeks, has to a large extent abolished the need for daily injections. Thirty milligrams of
SomatoStatin analogueS in PharmacotheraPy
Wouter W. de Herder
Department of Internal Medicine, Erasmus MC, Sector of Endocrinology, Rotterdam, The Netherlands
5.1
SOMATOSTATIN ANALOgueS IN PHARMACOTHeRAPy 167
lanreotide (Somatuline® PR; Ipsen, Paris, France) has to be administered intramuscu-larly every 10–14 days and roughly has an equal efficacy to octreotide [6]. A slow‐
release depot preparation of lanreotide, lanreotide Autogel® (Ipsen, Paris, France), has to be administered deep subcutaneously (s.c.) in dosages ranging from 60 to 120 mg once every 3–6 weeks [7, 8].
expression of somatostatin receptors by endocrine tumors is essential for the con-trol of hormonal hypersecretion by somatostatin analogues. In sst2‐ and/or sst5‐positive patients, clinical symptomatology can be controlled by the chronic administration of one of these currently available octapeptide somatostatin analogues [1, 9]. Octreotide (Sandostatin®) and lanreotide (Somatuline®) have been registered in most countries for the control of hormonal symptoms in patients with well‐differentiated neuroen-docrine tumors of the digestive tract (carcinoids) and pancreas and in patients with acromegaly [2, 5, 10]. These drugs may also exert antiproliferative effects on tumors in these patients [11, 12]. In patients with well‐differentiated neuroendocrine tumors of the digestive tract (carcinoids) and pancreas, treatment with very high doses of somato-statin analogues might induce more antiproliferative effects than relatively low doses [10, 13, 14]. In the past, treatment of these patients with ultrahigh‐dose octreotide pamoate (Onco‐LAR®; Novartis, Basel, Switzerland), of which 160 mg had to be admin-istered intramuscularly every 2–4 weeks, did show promising results [15]. However, the development of this drug was discontinued by the manufacturing company.
Pasireotide (SOM 230) is a somatostatin analogue that binds to all somatostatin receptor subtypes, except sst4 (Table 5.1.1) [16]. The drug is currently produced as a short‐acting formulation that has to be administered s.c. and a long‐acting intramus-cular LAR formulation. These drugs currently undergo phase III study programs in Cushing’s disease, acromegaly, and well‐differentiated neuroendocrine tumors of the digestive tract (carcinoids) and the pancreas [17–21]. Pasireotide is generally well tolerated, although impaired glucose tolerance and hyperglycemia can occur.
New fundamental insights in receptor physiology also opened the concept of mul-tireceptor family crosstalk, like between somatostatin and dopamine receptors. Focus has, therefore, been directed toward the development of new drugs interacting with these phenomena [22]. BIM‐23A760 (Ipsen, Paris, France) is a chimeric molecule that binds to sst2 and sst5 and dopamine receptor 2 [23]. However, in a phase IIb study in patients with acromegaly, this drug showed strong dopaminergic activity but only very weak somatostatinergic activity. On the basis of these preliminary data, the manufacturing company decided to discontinue the development of this drug.
table 5.1.1 Properties of somatostatin receptor subtypes
Binding affinity: IC50 value in nM (mean ± SeM)
Compound sst1 sst2 sst3 sst4 sst5
SS‐14 0.93–2.3 0.2–0.3 0.6–1.4 1.5–1.8 0.3–1.4
Lanreotide 180–2330 0.5–0.8 14–107 230–2100 5.2–17
Octreotide 280–1140 0.4–0.6 7.1–34.5 >1000 6.3–7.0
Pasireotide 9.3 1.0 1.5 >100 0.2
referenceS
[1] Lamberts, S. W.; van der Lely, A. J.; de Herder, W. W.; Hofland, L. J. New england Journal of Medicine 1996, 334, 246–254.
[2] Feelders, R. A.; Hofland, L. J.; van Aken, M. O.; et al. Drugs 2009, 69, 2207–2226.
[3] Patel, y. C. Frontiers in Neuroendocrinology 1999, 20, 157–198.
[4] Bauer, W.; Briner, u.; Doepfner, W.; et al. Life Sciences 1982, 31, 1133–1140.
[5] Oberg, K.; Kvols, L.; Caplin, M.; et al. Annals of Oncology 2004, 15, 966–973.
[6] Caron, P.; Cogne, M.; gusthiot‐Joudet, B.; Wakim, S.; Catus, F.; Bayard, F. european Journal of endocrinology 1995, 132, 320–325.
[7] Chanson, P.; Boerlin, V.; Ajzenberg, C.; et al. Clinical endocrinology (Oxford) 2000;
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[8] O’Toole, D.; Ducreux, M.; Bommelaer, g.; et al. Cancer 2000, 88, 770–776.
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[10] eriksson, B.; Oberg, K.; Andersson, T.; Lundqvist, g.; Wide, L.; Wilander, e.
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[11] Shojamanesh, H.; gibril, F.; Louie, A.; et al. Cancer 2002, 94, 331–343.
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[13] eriksson, B.; Renstrup, J.; Imam, H.; Oberg, K. Annals of Oncology 1997, 8, 1041–1044.
[14] Imam, H.; eriksson, B.; Lukinius, A.; et al. Acta Oncologica 1997, 36, 607–614.
[15] Welin, S. V.; Janson, e. T.; Sundin, A.; et al. european Journal of endocrinology 2004, 151, 107–112.
[16] Bruns, C.; Lewis, I.; Briner, u.; Meno‐Tetang, g.; Weckbecker, g. european Journal of endocrinology 2002, 146, 707–716.
[17] Kvols, L.; Oberg, K.; de Herder, W.; et al. Journal of Clinical Oncology (Meeting Abstracts) 2005, 23 (16 suppl), Abstract 8024.
[18] van der Hoek, J.; van der Lelij, A. J.; Feelders, R. A.; et al. Clinical endocrinology (Oxford) 2005, 63, 176–184.
[19] Feelders, R. A.; de Bruin, C.; Pereira, A. M.; et al. New england Journal of Medicine 2010, 362, 1846–1848.
[20] Schmid, H. A. Molecular and Cellular endocrinology 2008, 286, 69–74.
[21] Petersenn, S.; Schopohl, J.; Barkan, A.; et al. Journal of Clinical endocrinology and Metabolism 2010, 95(6), 2781–2789.
[22] Rocheville, M.; Lange, D. C.; Kumar, u.; Patel, S. C.; Patel, R. C.; Patel, y. C. Science 2000, 288, 154–157.
[23] Florio, T.; Barbieri, F.; Spaziante, R.; et al. endocrine‐Related Cancer 2008, 15, 583–596.
Somatostatin Analogues: From Research to Clinical Practice, First Edition. Edited by Alicja Hubalewska-Dydejczyk, Alberto Signore, Marion de Jong, Rudi A. Dierckx, John Buscombe, and Christophe Van de Wiele.
© 2015 John Wiley & Sons, Inc. Published 2015 by John Wiley & Sons, Inc.
AbbreviAtions
ACTH adrenocorticotrophic hormone, corticotrophin AE adverse event
ATG Autogel CAB cabergoline CI confidence interval D2R dopamine type 2 receptor FSH follicle-stimulating hormone fT3 free triiodothyronine fT4 free thyroxine GH growth hormone
GHRH growth hormone-releasing hormone HDL-C high-density lipoprotein cholesterol i.m. intramuscular
IGF-1 insulin-like growth factor type 1 LAN lanreotide
LAR long-acting release