Pasireotide: a novel treatment for patients with acromegaly

Figures & data

Table 1 Etiology of acromegaly

Etiology	Disease	Comments
Pituitary
Adenoma	Acromegaly (type 1, 2, or 3)	Common cause
Carcinoma	Malignant acromegaly	Extremely rare
Silent	GH-positive adenoma without hypersecretion or acromegaly
Somatotroph hyperplasia	Tumor-secreting ectopic GHRH
Empty sella tumor	GH-secreting tumor remnants arising in rim of pituitary tissue	No clear adenoma in MRI
Ectopic
Excess GH secretion	Aberrant GH-cell adenoma in sphenoid or parapharyngeal sinuses	Ectopic pituitary tissue remnants
	Ectopic GH-secreting tumor in pancreas or lymphoma	Very rare
Excess GHRH secretion	Hypothalamic hamartoma, choriostomas, gliomas, gangliocytomas
	Pancreatic islet cell tumors
	Bronchial and intestinal carcinoids
Mixed adenomas
GH plus PRL	Acidophil stem cells tumors
GH plus PRL, ACTH, or rarely TSH	Plurihormonal GH-cell adenomas
Genetic mutations and familial acromegaly
GH-secreting pituitary adenoma	MEN-1	Rare
	Carney complex	Rare
	McCune–Albright syndrome	Rare. Associated with pituitary hyperplasia
	FIPA	<5%
	Isolated familial somatotropinomas	Younger patients
	PRKAR1A gene mutations	Rare
	AIP mutation
	X-linked acrogigantism	GPR101 mutation
Iatrogenic	GH exogenous administration

Abbreviations: GH, growth hormone; GHRH, growth hormone-releasing hormone; MRI, magnetic resonance imaging; PRL, prolactin; ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone; MEN-1, multiple endocrine neoplasia type 1; FIPA, familial isolated pituitary adenomas; PRKAR1A, protein kinase cAMP-dependent, regulatory, type 1 α; AIP, aryl hydrocarbon receptor-interacting protein; GPR101, G-protein-coupled receptor 101.

Figure 1 Somatostatin and pasireotide structure.

Notes: The two somatostatin isoforms in humans are depicted on the left side. Somatostatin (SST) is a cyclical peptide of 14 (SST-14) or 28 (SST-28) amino acids. Essential functional groups of the SST peptide with high-binding affinity to SSTRs were detected using the alanine scanning technology. Incorporation of four synthetic and two essential amino acids of SST in the form of a novel basic trans-(L)-hydroxyproline aminoethyl-urethane extension, phenylglycine, O-benzyl-tyrosine, and D-Trp to corresponding positions into a stable cyclohexapeptide template resulted in SOM230 or pasireotide, a multireceptor SRL (right side). Adapted from Cuevas-Ramos D, Fleseriu M. Somatostatin receptor ligands and resistance to treatment in pituitary adenomas. J Mol Endocrinol. 2014;52:R223–R240. Copyright © 2014, Society for Endocrinology.⁹²
Abbreviations: SST, somatostatin; SSTR, somatostatin receptor; SRL, somatostatin receptor ligand.

Table 2 Medical therapy for acromegaly that is commercially available and in different stages of clinical research

Drug	Mechanism of action	Commercial or research name
Clinically available
Octreotide and octreotide LAR	Predominantly SSTR2 SRL	Sandostatin
		Sandostatin LAR/LAR depot
Lanreotide, lanreotide SR, and lanreotide autogel	Predominantly SSTR2 SRL	Somatuline autogel
Pasireotide LAR	SSTR5 > SSTR2 > SSTR3 > SSTR1 multireceptor SRL	Signifor LAR
Pegvisomant	GH-receptor antagonist	Somavert
Cabergoline	D2DR agonist	Dostinex
Bromocriptine	D2DR agonist	Parlodel
Clinical research
Oral octreotide	Predominantly SSTR2 SRL	Octreolin
Long-acting octreotide implants	Predominantly SSTR2 SRL	–
Long-acting SC octreotide	Predominantly SSTR2 SRL	CAM2029
Antisense oligonucleotide	Directed to the GH receptor	COR-004
Somatoprim	SSTR2, SSTR4, and SSTR5 multireceptor SRL	COR-005
Botulinum neurotoxin-derived targeted GH secretion inhibitor	GH secretion inhibitor	–

Abbreviations: LAR, long-acting release; SSTR, somatostatin receptor; SRL, somatostatin receptor ligand; SR, slow release; D2DR, D2 dopamine receptor; SC, subcutaneous; GH, growth hormone.

Figure 2 Pasireotide effects.

Notes: The novel multireceptor SRL pasireotide is a stable cyclohexapeptide with high affinity for SSTR5 > SSTR2 > SSTR3 > SSTR1 (blue arrows). The main effect after binding to SSTRs in patients with acromegaly is to decrease GH secretion and induce tumor shrinkage (red arrows).
Abbreviations: SRL, somatostatin receptor ligand; SSTR, somatostatin receptor; GH, growth hormone; GLP-1, glucagon-like peptide 1; CYP450, cytochrome P450.

Table 3 Potential drug interactions with pasireotide LAR

Mechanism of action	Drug	Adverse effect
Antiarrhythmics	Amiodarone, propafenone	QT prolongation, cardiac arrhythmias, bradycardia
Anxiolytics or antidepressants	Amitriptyline, imipramine, citalopram	QT prolongation, cardiac arrhythmias
Antibiotics	Azithromycin, ciprofloxacin, erythromycin	QT prolongation, cardiac arrhythmias
Antimicotic	Fluconazole	QT prolongation, cardiac arrhythmias
Beta-blockers	Sotalol, atenolol, metoprolol	Bradycardia, hypotension, cardiac conduction disturbance
Calcium channel blockers	Verapamil	Bradycardia, hypotension, cardiac conduction disturbance
Hypoglycemic agents	Acarbose, glyburide, glipizide	Reduce hypoglycemic agent efficacy
Dopamine agonists	Bromocriptine	Hypotension
Steroids	Prednisone, hydrocortisone	QT prolongation
Immune system suppressors	Cyclosporine	Decrease cyclosporine levels
Contraindicated	Cisapride, dronedarone, pimozide, quinine, saquinavir, thioridazine, toremifene	QT prolongation, cardiac arrhythmias

Abbreviation: LAR, long-acting release.

Cuevas-RamosDFleseriuMSomatostatin receptor ligands and resistance to treatment in pituitary adenomasJ Mol Endocrinol201452R223R24024647046

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