Pasireotide

Where octreotide is essentially an SSTR2 drug, pasireotide binds four of the five somatostatin receptor subtypes and has roughly 40-fold higher SSTR5 affinity than octreotide. Corticotroph adenomas in Cushing's disease express SSTR5 heavily, which is why pasireotide lowers ACTH and cortisol where SSTR2-selective analogues do not. The same broad binding explains the drug's biggest liability: SSTR5 activation on pancreatic beta cells and the suppression of GLP-1 and GIP release produce hyperglycaemia in the majority of patients, often severe enough to require metformin or a DPP-4 inhibitor from the start.

Targets: SSTR5, SSTR2, SSTR1, SSTR3, ACTH secretion, Growth hormone secretion

• · Start 0.6 or 0.9 mg twice daily; titrate between 0.3 and 0.9 mg twice daily on urinary free cortisol and tolerability.
• · Start 40 mg every 4 weeks for acromegaly (10 mg for Cushing's), titrate to a maximum of 60 mg.

Work out your exact syringe units →

• very commonHyperglycaemia and new-onset diabetes— Occurs in roughly three quarters of patients and is the main reason for discontinuation.
• very commonDiarrhoea and nausea— Class effect, usually early.
• commonCholelithiasis— As with other somatostatin analogues.
• uncommonQT prolongation— Baseline ECG and electrolytes are part of the label.
• uncommonHypocortisolism from over-suppression— Patients need to recognise adrenal insufficiency symptoms.

• Severe hepatic impairment (Child-Pugh C)
• Uncontrolled diabetes without a plan to intensify glucose therapy
• Congenital long QT syndrome or uncorrected hypokalaemia and hypomagnesaemia

• cautioninsulin-icodec — Insulin requirements typically rise sharply because pasireotide blocks insulin and incretin secretion.
• redundantoctreotide — An alternative in the same class, chosen when SSTR2-selective drugs fail.

• · Fasting glucose weekly for the first 3 months, then HbA1c quarterly
• · 24-hour urinary free cortisol or late-night salivary cortisol
• · IGF-1 in acromegaly
• · ECG, potassium and magnesium at baseline
• · Liver enzymes and gallbladder imaging

Prescription drug approved in the US and EU.

• Signifor and Signifor LAR FDA prescribing information (label)
• Colao et al. 2012 NEJM, randomised trial of pasireotide in Cushing's disease (trial)
• Gadelha et al. 2014 Lancet Diabetes Endocrinology, PAOLA trial of pasireotide LAR in inadequately controlled acromegaly (trial)

The clinically decisive fact is in the binding table: pasireotide's IC50 at SSTR5 is 0.16 nM, tighter than somatostatin-14's own 0.29 nM, while octreotide barely touches SSTR5. Corticotroph adenomas in Cushing's disease express SSTR5 densely and SSTR2 sparsely, and glucocorticoid excess downregulates SSTR2 further, which is precisely why SSTR2-selective analogues fail in Cushing's and pasireotide does not. Downstream the signalling is conventional Gi coupling, reducing cyclic AMP and calcium influx in the corticotroph and thereby POMC transcription and ACTH secretion. The hyperglycaemia is not a side effect in the usual sense, it is the same receptor doing its job in the wrong tissue. SSTR5 sits on pancreatic beta cells and on intestinal L and K cells, so pasireotide suppresses insulin secretion directly and simultaneously cuts GLP-1 and GIP release, removing the incretin amplification of insulin. Glucagon is comparatively spared. The result is falling insulin secretion without a matching fall in glucagon, which is the physiology of type 2 diabetes, and it appears within days. That mechanism also dictates the fix: incretin-based therapy, a DPP-4 inhibitor or a GLP-1 receptor agonist, works better here than agents acting elsewhere, because you are replacing the specific signal the drug removed.

Almost everything that goes wrong with pasireotide is glucose. Three quarters of patients develop hyperglycaemia, it starts within the first fortnight, and clinicians who wait for the three-month HbA1c end up with a patient in the teens. The second failure mode is the mirror image: over-suppression of cortisol producing adrenal insufficiency in someone who has never in their life had too little cortisol and does not recognise the symptoms. Third, QT prolongation on a background of unchecked hypokalaemia. Fourth, the LAR suspension has the usual depot handling constraints: room temperature for at least 30 minutes, mix and inject immediately, deep gluteal. Fifth, patients who improve dramatically in the first two months and then plateau are often escalated past the point of benefit, buying more hyperglycaemia for no further cortisol reduction.

1. 600 mcgWeeks 1-2, Cushing's disease, immediate-release — 0.6 mg subcutaneously twice daily. Some centres start at 0.9 mg twice daily in more severe disease.
2. 900 mcgFrom week 2, on tolerability — 0.9 mg twice daily is the maximum immediate-release dose. If urinary free cortisol is normal but glucose is a problem, go down to 0.3 mg twice daily instead.
3. 10 mgMonth 1, Signifor LAR for Cushing's disease — 10 mg intramuscularly every 4 weeks as the Cushing's starting depot dose.
4. 40 mgMonth 1, Signifor LAR for acromegaly — 40 mg intramuscularly every 4 weeks is the acromegaly starting dose, deliberately higher than the Cushing's start.
5. 60 mgMonth 4 onward — 60 mg every 4 weeks is the ceiling for both indications. Escalate only if biochemistry demands it and glucose is manageable.

• SSTR5 — IC50 0.16 +/- 0.01 nM (Signifor LAR label, Table 4)

  The defining target. Suppresses ACTH release from corticotroph adenomas, contributes to GH suppression, and on beta cells and enteroendocrine cells suppresses insulin, GLP-1 and GIP, producing the hyperglycaemia.

• SSTR2 — IC50 1.0 +/- 0.1 nM

  Conventional suppression of GH and gut hormone secretion; weaker than octreotide at this receptor.

• SSTR3 — IC50 1.5 +/- 0.3 nM

  Engaged at clinical concentrations and linked in vitro to apoptotic signalling in tumour cells.

• SSTR1 — IC50 9.3 +/- 0.1 nM

  Weak but real binding, unlike octreotide which is essentially inactive here.

• SSTR4 — IC50 greater than 100 nM

  Not clinically engaged.

• Colao 12-month phase 3 study of pasireotide in Cushing's disease Phase 3, randomised, dose-blind · n=162 · 52 weeks · 2012

  Normal urinary free cortisol at month 6 without dose escalation: 12 patients in the 600 mcg twice-daily group and 21 in the 900 mcg twice-daily group. Cortisol fell about 50 percent by month 2 and stayed down. Hyperglycaemia-related adverse events occurred in 118 of 162 patients and 74 needed glucose-lowering drugs started.

• PAOLA Phase 3, randomised, open-label, three-arm · 2014

  Biochemical control in acromegaly inadequately controlled on octreotide LAR or lanreotide. Pasireotide LAR at 40 mg and 60 mg both beat continued first-generation analogue therapy.

Urinary free cortisol falls fast, with about half the total reduction achieved by month 2 in the phase 3 data. Hyperglycaemia appears faster than the efficacy does, typically within one to two weeks. In acromegaly IGF-1 is assessed at 3 months and LAR reaches steady state after about three monthly injections. If urinary free cortisol has not moved at all by month 2, the drug is unlikely to work in that patient.

Pasireotide should be assumed to arrive with a diabetes regimen attached. The mechanistically correct partners are metformin first, then a DPP-4 inhibitor or a GLP-1 receptor agonist, because the hyperglycaemia comes from suppressed insulin and suppressed incretin secretion rather than insulin resistance. SGLT2 inhibitors are a reasonable third line. Insulin works but requirements can climb steeply. In Cushing's disease it combines rationally with cabergoline and with osilodrostat or ketoconazole, hitting the axis at pituitary and adrenal simultaneously, which often achieves control at pasireotide doses that are tolerable. Do not combine with octreotide or lanreotide. Avoid stacking with other QT-prolonging drugs, and treat anything that wastes potassium or magnesium, loop diuretics included, as part of the QT risk.

Against octreotide and lanreotide: broader-spectrum and stronger where SSTR2 selectivity fails, and the only somatostatin analogue with a Cushing's disease indication. It buys that with a hyperglycaemia rate no first-generation analogue approaches. Against osilodrostat and metyrapone in Cushing's disease: those are adrenal steroidogenesis inhibitors that work regardless of receptor expression and control cortisol more reliably, but they do nothing to the tumour and carry their own adrenal insufficiency and androgen-excess problems. Against pituitary surgery: surgery remains first-line and pasireotide is what you reach for when surgery has failed or is not possible. Against pegvisomant in acromegaly: pegvisomant normalises IGF-1 more reliably but is not tumour-directed, whereas pasireotide is.

$8000–$20000/month. Unverified estimate of US list pricing for Signifor LAR. Not sourced in this session; the real figure depends entirely on specialty pharmacy and patient assistance arrangements.

• ?The three-letter structure given is the conventional description of pasireotide's cyclohexapeptide, but I did not resolve a primary structural source this session, so verified is false.
• ?Absolute bioavailability of subcutaneous or intramuscular pasireotide is not stated in the accessible label sections.
• ?Volume of distribution is recorded as 100 L because the label says only that Vz/F exceeds 100 L; the true value is higher and unquantified.
• ?PAOLA's enrolment and exact duration were not confirmed against the paper.
• ?The 84-day time to steady state is derived from the label statement that steady state follows three monthly doses.
• ?Cost figures are unverified estimates.

• A 12-month phase 3 study of pasireotide in Cushing's disease Colao A, et al., New England Journal of Medicine, 2012 · PMID 22397653

  The registration trial. The hyperglycaemia numbers in the abstract are as stark as the efficacy numbers, which is the honest way to read this drug.

• Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial Gadelha MR, et al., Lancet Diabetes & Endocrinology, 2014 · PMID 25260838

  Establishes pasireotide as the second-line option after first-generation analogues fail.

• SIGNIFOR LAR (pasireotide) for injectable suspension - FDA prescribing information Recordati Rare Diseases, DailyMed

  Source of the SSTR1-5 IC50 table quoted above, plus 88 percent protein binding, Vz/F over 100 L, and the 48 percent faecal and 8 percent urinary recovery.