Pharmacokinetics, pharmacodynamics, and safety of pasireotide LAR in patients with acromegaly: A randomized, multicenter, open‐label, phase I study

Abstract

Pasireotide (SOM230), a multireceptor-targeted somatostatin analogue, has exhibited favorable safety/tolerability in several clinical studies. A long-acting-release (LAR) formulation of pasireotide may offer advantages over the subcutaneous formulation. This randomized, open-label, Phase I study evaluated the safety, PK, and PD of pasireotide LAR 20, 40, or 60 mg/month in patients with acromegaly. Safety assessments and blood samples for PK and PD were taken at designated time points. Thirty-five patients were randomized and completed the study. Steady-state pasireotide concentrations were achieved following three monthly injections. Trough pasireotide concentrations (ng/mL) 28 days after each injection were: 2.48, 4.16, and 3.10 (20 mg group); 6.42, 6.62, and 7.12 (40 mg group); and 9.51, 11.7, and 13.0 (60 mg group). At study end, 51% and 57% of patients achieved GH levels ≤2.5 μg/L and IGF-1 levels below ULN, respectively. Compared with baseline, fasting blood glucose and HbA1c levels increased, whereas fasting blood insulin levels decreased. Acromegaly symptoms were generally improved. Adverse events were mostly gastrointestinal and mild/moderate. Pasireotide LAR was generally well tolerated. Steady-state PK was achieved after three monthly doses; exposures were approximately dose proportional. Control of GH, IGF-1, and symptoms improved, suggesting that pasireotide LAR may be an effective treatment for acromegaly.

60 YEARS OF NEUROENDOCRINOLOGY: Acromegaly

“…Both pasireotide (Petersenn et al 2014a) and pasireotide LAR (Petersenn et al 2014b) appear promising as medical agents with antisecretory and antitumoral effect. A comparison between pasireotide LAR 40 mg/28 days and OCT-LAR 20 mg/28 days revealed that biochemical control (GH !2.5 mg/l and normal IGF1) after 12 months was achieved in significantly more cases treated with pasireotide LAR than with OCT-LAR (31% vs 19%).…”

“…Rare complications of SRS are cranial nerves deficits, headache, radiation necrosis, carotid artery stenosis, and trigeminal neuralgia (Beauregard et al 2003, Stapleton et al 2010. The risk of visual complications limits the use of SRS to lesions more than 3 mm away from the optic structures (Petrovich et al 2003). To date, if RT is indicated, stereotactic methods should be applied, unless the tumor remnant is large or close to the optic apparatus (Katznelson et al 2014).…”

Pasireotide in Acromegaly: A Review

“…Following a washout period if prior medical therapy had been used, pasireotide was administered once every month for 3 months. At day 91, 51 % of patients across all groups had mean GH levels of B2.5 lg/L (compared with 11 % at baseline), and over the 3-month period, mean GH levels had decreased by 67, 60 and 63 % in groups receiving pasireotide 20, 40 or 60 mg, respectively [12]. At month 3, mean serum IGF-1 levels had decreased to below the upper limit of normal (ULN) in 57 % of patients, and decreases from baseline of 40, 51 and 50 % were observed in each group, respectively.…”

“…GH and IGF-1 levels were rapidly suppressed following the first intramuscular injection of pasireotide 20, 40 or 60 mg, and suppression was maintained throughout treatment in a randomised, phase I study in patients with acromegaly (n = 35) [12]. Following a washout period if prior medical therapy had been used, pasireotide was administered once every month for 3 months.…”

“…Pasireotide (the subcutaneous and intramuscular formulations) effectively reduces GH levels in a generally dose dependent manner in patients with acromegaly [10][11][12][13]. In a randomized, crossover, phase II study in patients (n = 60) who had previously received medical therapy for acromegaly and those who had not, more than a quarter of all patients achieved biochemical control (GH \2.5 lg/L and normalized IGF-1 for age and sex) after 3 months of subcutaneous pasireotide 200, 400 or 600 lg twice daily (each dose was given for 4 weeks) subsequent to completing 4 weeks' treatment with octreotide 100 lg three times daily [13].…”