Pharmacokinetic-pharmacodynamic comparison of a novel multiligand somatostatin analog, SOM230, with octreotide in patients with acromegaly

Ma, Pelosi; Wang, Yanfeng; Hoek, Joost van der; Nedelman, Jerry; Schran, Horst; Tran, Ly‐Le; Lamberts, Steven W. J.

doi:10.1016/j.clpt.2005.04.003

Cited by 60 publications

(39 citation statements)

References 16 publications

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“…The AUC was ninefold higher with pasireotide (2326G323 ng !h/ml) than with octreotide (273G13 ng!h/ml), and the calculated clearance of pasireotide was 226G27 ml/h per kg, compared with 1843G84 ml/h per kg for octreotide. These data confirm the superior bioavailability of pasireotide vs octreotide in rats, as previously demonstrated in patients with acromegaly (Ma et al 2005).…”

Section: Acute Effects Of High-dose Pasireotide On Plasma Glucosesupporting

confidence: 77%

Effects of somatostatin analogs on glucose homeostasis in rats

Schmid

Brueggen²

2011

Journal of Endocrinology

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Pasireotide (SOM230) is a multireceptor-targeted somatostatin analog with high binding affinity for sstr 1,2,3 and sstr 5 . The effects of pasireotide and octreotide on blood glucose, insulin, and glucagon levels in rats were evaluated alone and in combination. Single-dose s.c. pasireotide acutely elevated plasma glucose, whereas single-dose s.c. octreotide had no or a small hypoglycemic effect. Glucose elevation with s.c. pasireotide was transient with tachyphylaxis after repeated or continuous administration. Pasireotide and octreotide caused similar inhibitory effects on insulin secretion, whereas pasireotide had a weaker inhibitory effect on glucagon secretion than octreotide. Continuous infusion of pasireotide or injection of pasireotide long-acting release (LAR) resulted in only small and transient elevations of plasma glucose. Based on these results, and differences in the sstr binding affinity of pasireotide vs octreotide, it was hypothesized that the sstr 5 vs sstr 2 receptor activation ratio is the main driver of hyperglycemia after pasireotide. The results also suggest that stronger activation of sstr 2 may counteract the hyperglycemic effect. Indeed, co-administration of octreotide, which has a high affinity for sstr 2 , with a hyperglycemic dose of pasireotide did not cause significant changes in plasma glucose levels. In conclusion, although pasireotide and octreotide inhibited insulin to a similar degree, only pasireotide administration was associated with hyperglycemia. The strong glucagon inhibitory effect exhibited by octreotide but not pasireotide may explain this observation. The lack of hyperglycemia during co-administration of pasireotide and octreotide may be explained by the greater activation of sstr 2 compared with pasireotide alone, causing the insulinglucagon balance to shift within the normoglycemic range. Extrapolation of these data to humans must account for species differences in islet cell sstr expression.

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Section: Acute Effects Of High-dose Pasireotide On Plasma Glucosesupporting

confidence: 77%

Effects of somatostatin analogs on glucose homeostasis in rats

Schmid

Brueggen²

2011

Journal of Endocrinology

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“…This may also explain the lower potency of SOM230 compared to octreotide in patients with acromegaly. The test drug concentration levels, at which half of the maximum drug effect is observed (EC50), are 46 and 553 pg/ml for octreotide and SOM230 with considerable interpatient variability, mainly attributable to the heterogeneous responses among acromegalic patients (40). Although the overall effects of octreotide and SOM230 on the stimulation of p27 and inhibition of pERK1/2 were not significantly different in our human samples, the variable effects of octreotide and SOM230 on the individual human samples can be explained by several mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours

et al. 2006

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Objectives: Somatostatin (SST) analogues play an important role in the medical management of somatotroph pituitary adenomas and new agonists have the potential to be effective in a wider group of pituitary and other tumours. The anti-proliferative effect of SST occurs through multiple mechanisms, one of which is cell-cycle arrest, where p27, a cyclin-dependent kinase inhibitor, is an important regulator. We hypothesised that SST may upregulate p27 protein levels and downregulate the MAP kinase pathway in these tumours. Methods: Human pituitary adenoma cells and rat pituitary cell line (GH3) were cultured and treated in vitro with octreotide and the broad-spectrum SST agonist SOM230 (pasireotide). Immunoblotting for p27 and phospho-ERK (pERK) was performed and proliferation assessed by [3 H]-thymidine incorporation. Histological samples from acromegalic patients treated with octreotide before surgery were immunostained for p27 and compared to samples from untreated patients matched for sex, age, tumour size, extension and invasiveness. Results: We detected upregulation of p27 protein levels with SST analogue treatment in vitro in human pituitary adenoma samples. pERK1/2 was inhibited by SST analogues in both the human samples and GH3 cells. SST and its analogues inhibited the proliferation of GH3 cells. p27 immunostaining was stronger in samples from patients with longer preoperative octreotide treatment (more than 6 months) than in samples from patients with shorter treatment periods. Conclusions: This study demonstrates that SST-mediated growth inhibition is associated with the downregulation of pERK and upregulation of p27. More potent and broader-spectrum SST analogues are likely to play an increasing role in the treatment of tumours, where the MAP kinase pathway is overactivated.

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“…The distinct affinity profile of each SSA translates into specific pharmacological properties (10,11,12). Octreotide and Lanreotide bind with a high affinity at sub-nanomolar concentration to sst2.…”

Section: Introductionmentioning

confidence: 99%

DG3173 (somatoprim), a unique somatostatin receptor subtypes 2-, 4- and 5-selective analogue, effectively reduces GH secretion in human GH-secreting pituitary adenomas even in Octreotide non-responsive tumours

Plöckinger

Hoffmann²,

Geese³

et al. 2012

European Journal of Endocrinology

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Objective: Somatostatin analogues (SSA) reduce autonomous GH secretion by activating somatostatin receptors (sst) 2 and 5 in 50-60% of acromegalic patients. However, by inhibiting insulin secretion these SSA reduce glucose tolerance. DG3173 is a novel SSA with additional binding to sst4 and low insulin-suppressing activity. We investigated the effect of DG3173, including its relation to specific tumour characteristics, on GH secretion in human somatotroph adenoma cell cultures (hSA) in comparison with Octreotide. Methods: Twenty-seven hSA were characterised immunohistochemically for their hormone-and sstexpression, granularity and pre-surgical therapy with SSA. GH was determined in supernatants of hSA treated with DG3173 or Octreotide in time-(nZ6) and dose-response (nZ21) experiments. A positive response was defined as GH suppression to below 80% of baseline. Results: In the dose-response experiments DG3173 suppressed GH secretion in more adenomas than Octreotide (10/21 vs 5/21), including 38% (6/16) of Octreotide non-responders. In responders the extent of GH suppression and IC 50 were comparable for both SSA. The response-rate of both SSA was higher in monohormonal vs bihormonal adenomas, yet GH declined similarly in both groups. Neither pre-surgical SSA (nZ6) nor tumour morphology was related to the GH response. However, semiquantitative analysis indicated a small but significant negative correlation between the GH response to Octreotide and the immunoreactivity scores of sst2 expression. Conclusions: DG3173 equalled Octreotide in suppressing GH secretion in hSA. Since DG3173 suppressed GH in some Octreotide-non-responsive adenomas, its clinical effectiveness will be worth testing. Moreover, its reduced insulin-suppressive potency would make it a valuable alternative to Octreotide.

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Pharmacokinetic-pharmacodynamic comparison of a novel multiligand somatostatin analog, SOM230, with octreotide in patients with acromegaly

Cited by 60 publications

References 16 publications

Effects of somatostatin analogs on glucose homeostasis in rats

Effects of somatostatin analogs on glucose homeostasis in rats

Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours

DG3173 (somatoprim), a unique somatostatin receptor subtypes 2-, 4- and 5-selective analogue, effectively reduces GH secretion in human GH-secreting pituitary adenomas even in Octreotide non-responsive tumours

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