sst1 ( pKi = 8.2 ); sst2 ( pKi = 9.0 ); sst3 ( pKi = 9.1 ); sst4 ( pKi < 7.0 ); sst5 ( pKi = 9.9 )

Pasireotide binds to human somatostatin receptors with a unique high affinity (subtypes sst1/2/3/4/5, pKi=8.2/9.0/9.1/<7.0/9.9, respectively)[1].
Pasireotide suppresses the growth hormone releasing hormone (GHRH)-induced release of growth hormone (GH) in primary cultures of rat pituitary cells, with an IC50 of 0.4 nM[1].

Pasireotide (160 mg/kg/mouth; s.c. for 4 months) dramatically lowers serum insulin, raises serum glucose, shrinks tumor size, and accelerates apoptosis in Pdx1-Cre[2].
Pasireotide (2-50 μg/kg; s.c. twice daily for 42 days) acts through the SSTR2 receptor to produce antinociceptive and anti-inflammatory effects in a mouse model of immune-mediated arthritis[4].

12 month-old conditional Men1 knockout mice with insulinoma
160 mg/kg/mouth
S.c. every month for 4 months

Absorption, Distribution and Excretion
The peak plasma concentration of pasireotide occurs in 0.25-0.5 hours. After administration of single and multiple doses, there is dose-proportionoal increases in Cmax and AUC.
Pasireotide is eliminated mostly by hepatic clearance (biliary excretion)(about 48%) with some minor renal clearance (about 7.63%).
Pasireotide is widely distributed and has a volume of distribution of >100L.
The clearance in healthy patient is ~7.6 L/h and in Cushing’s disease patients is ~3.8 L/h.

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Metabolism / Metabolites
Metabolism is minimal.

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Biological Half-Life
The half-life is 12 hours.

Hepatotoxicity
Mild, transient, asymptomatic elevations in serum aminotransferase levels occur in up to 29% of patients receiving pasireotide LAR, but elevations above 5 times the upper limit of normal are rare (
Pasireotide causes inhibition of gall bladder contractility and a decrease in bile secretion, and long term therapy is associated with a high rate of cholesterol gallstone formation. In prospective studies, between 20% and 30% of patients with acromegaly treated with maintenance pasireotide for one to two years developed gallstones detected by ultrasonography and a proportion developed symptomatic cholelithiasis requiring hospitalization and cholecystectomy. Even after cholecystectomy, cholesterol stones may form in the common bile duct and intrahepatic ducts during somatostatin analogue therapy which can cause symptoms and liver test abnormalities. Therapy with ursodiol does not appear to prevent gallstone formation related to somatostatin analogue therapy, although it may help.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent hepatobiliary injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
The excretion of pasireotide into breastmilk has not been studied. However, because it has a high molecular weight of 1047 daltons it is likely to be poorly excreted into breastmilk and it is a peptide that is likely digested in the infant's gastrointestinal tract. It is unlikely to reach the clinically important levels in infant serum. However, the manufacturer states that nursing mothers should not use pasireotide. An alternate drug is preferred.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Plasma protein binding is 88%.

[1]. A novel somatostatin mimic with broad somatotropin release inhibitory factor receptor binding and superior therapeutic potential. J Med Chem. 2003 Jun 5;46(12):2334-44.

[2]. Pasireotide (SOM230) is effective for the treatment of pancreatic neuroendocrine tumors (PNETs) in a multiple endocrine neoplasia type 1 (MEN1) conditional knockout mouse model. Surgery. 2012 Dec;152(6):1068-77.

[3]. Pasireotide (SOM230): development, mechanism of action and potential applications. Mol Cell Endocrinol. 2008 May 14;286(1-2):69-74.

[4]. Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune-mediated arthritis. Arthritis Rheum. 2011 Aug;63(8):2352-62.

Pasireotide is a six-membered homodetic cyclic peptide composed from L-phenylglycyl, D-tryptophyl, L-lysyl, O-benzyl-L-tyrosyl, L-phenylalanyl and modified L-hydroxyproline residues joined in sequence. A somatostatin analogue with pharmacologic properties mimicking those of the natural hormone somatostatin; used (as its diaspartate salt) for treatment of Cushing's disease. It has a role as an antineoplastic agent. It is a homodetic cyclic peptide and a peptide hormone. It is a conjugate base of a pasireotide(2+).
Pasireotide is a synthetic long-acting cyclic hexapeptide with somatostatin-like activity. It is marketed as a diaspartate salt called Signifor, which is used in the treatment of Cushing's disease.
Pasireotide is a Somatostatin Analog. The mechanism of action of pasireotide is as a Somatostatin Receptor Agonist.
Pasireotide is a synthetic polypeptide analogue of somatostatin that resembles the native hormone in its ability to suppress levels and activity of growth hormone, insulin, glucagon and many other gastrointestinal peptides. Because its half-life is longer than somatostatin, pasireotide can be used clinically to treat neuroendocrine pituitary tumors that secrete excessive amounts of growth hormone causing acromegaly, or adrenocorticotropic hormone (ACTH) causing Cushing disease. Pasireotide has many side effects including suppression of gall bladder contractility and bile production, and maintenance therapy can cause cholelithiasis and accompanying elevations in serum enzymes and bilirubin.
Pasireotide is a synthetic long-acting cyclic peptide with somatostatin-like activity. Pasireotide activates a broad spectrum of somatostatin receptors, exhibiting a much higher binding affinity for somatostatin receptors 1, 3, and 5 than octreotide in vitro, as well as a comparable binding affinity for somatostatin receptor 2. This agent is more potent than somatostatin in inhibiting the release of human growth hormone (HGH), glucagon, and insulin.
See also: Pasireotide Diaspartate (is active moiety of); Pasireotide Pamoate (is active moiety of).

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Drug Indication
For the treatment of Cushing’s disease, specifically for those patients whom pituitary surgery has not been curative or is not an option.
FDA Label
Signifor is indicated for the treatment of adult patients with Cushing's disease for whom surgery is not an option or for whom surgery has failed. Signifor is indicated for the treatment of adult patients with acromegaly for whom surgery is not an option or has not been curative and who are inadequately controlled on treatment with another somatostatin analogue.
Treatment of acromegaly and pituitary gigantism
Overproduction of pituitary ACTH, Pituitary dependant Cushing's disease, Pituitary dependant hyperadrenocorticism

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Mechanism of Action
Pasireotide activates a broad spectrum of somatostatin receptors, exhbiting a much higher binding affinity for somatostatin receptors 1, 3, and 5 than octreotide in vitro, as well as a comparable binding affinity for somatostatin receptor 2. The binding and activation of the somatostatin receptors causes inhibition of ACTH secretion and results in reduced cortisol secretion in Cushing's disease patients. Also this agent is more potent than somatostatin in inhibiting the release of human growth hormone (HGH), glucagon, and insulin.

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Pharmacodynamics
Signifor® is an analogue of somatostatin that promotes reduced levels of cortisol secretion in Cushing's disease patients.

C58H66N10O9

1047.2062535286

1046.501

C, 66.52; H, 6.35; N, 13.38; O, 13.75

396091-73-9

Pasireotide acetate; 396091-76-2; Pasireotide ditrifluoroacetate; Pasireotide L-aspartate salt; 396091-77-3; Pasireotide pamoate; 396091-79-5; Pasireotide (diaspartate); 1421446-02-7; 820232-50-6 (diaspartate)

9941444

Solid powder

1.4±0.1 g/cm3

1351.4±65.0 °C at 760 mmHg

771.1±34.3 °C

0.0±0.3 mmHg at 25°C

1.680

2.79

9

11

18

77

1940

7

NCCCC[C@@H](C(N[C@H]1CC2=CC=C(C=C2)OCC3=CC=CC=C3)=O)NC([C@H](NC([C@H](C4=CC=CC=C4)NC([C@H]5N(C([C@H](CC6=CC=CC=C6)NC1=O)=O)C[C@H](OC(NCCN)=O)C5)=O)=O)CC7=CNC8=C7C=CC=C8)=O

VMZMNAABQBOLAK-DBILLSOUSA-N

InChI=1S/C58H66N10O9/c59-27-13-12-22-46-52(69)64-47(30-38-23-25-42(26-24-38)76-36-39-16-6-2-7-17-39)53(70)66-49(31-37-14-4-1-5-15-37)57(74)68-35-43(77-58(75)61-29-28-60)33-50(68)55(72)67-51(40-18-8-3-9-19-40)56(73)65-48(54(71)63-46)32-41-34-62-45-21-11-10-20-44(41)45/h1-11,14-21,23-26,34,43,46-51,62H,12-13,22,27-33,35-36,59-60H2,(H,61,75)(H,63,71)(H,64,69)(H,65,73)(H,66,70)(H,67,72)/t43-,46+,47+,48-,49+,50+,51+/m1/s1

[(3S,6S,9S,12R,15S,18S,20R)-9-(4-aminobutyl)-3-benzyl-12-(1H-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-15-phenyl-6-[(4-phenylmethoxyphenyl)methyl]-1,4,7,10,13,16-hexazabicyclo[16.3.0]henicosan-20-yl] N-(2-aminoethyl)carbamate

Pasireotide free base; SOM230; SOM-230; SOM 230; trade name: Signifor; Signifor LAR

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~100 mg/mL (~95.5 mM)
Ethanol: ~100 mg/mL

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)