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Herbert A Schmid - One of the best experts on this subject based on the ideXlab platform.

  • Pasireotide treatment does not modify hyperglycemic and corticosterone acute restraint stress responses in rats.
    Stress (Amsterdam Netherlands), 2018
    Co-Authors: Antônio Ribeiro-oliveira, Herbert A Schmid, Junia Ribeiro De Oliveira Longo Schweizer, Pedro H. S. Amaral, Mariana F. Bizzi, Warley Cezar Da Silveira, Daniel T. A. Espirito-santo, Giancarlo Pereira Zille, Beatriz Santana Soares, Kevin C J Yuen
    Abstract:

    Pasireotide is a new-generation somatostatin analog that acts through binding to multiple somatostatin receptor subtypes. Studies have shown that Pasireotide induces hyperglycemia, reduces glucocorticoid secretion, alters neurotransmission, and potentially affects stress responses typically manifested as hyperglycemia and increased corticosterone secretion. This study specifically aimed to evaluate whether Pasireotide treatment modifies glucose and costicosterone secretion in response to acute restraint stress. Male Holtzman rats of 150-200 g were treated with Pasireotide (10 µg/kg/day) twice-daily for two weeks or vehicle for the same period. Blood samples were collected at baseline and after 5, 10, 30, and 60 min of restraint stress. The three experimental groups comprised of vehicle + restraint (VEHR), Pasireotide + restraint (PASR), and Pasireotide + saline (PASNR). Following Pasireotide treatment, no significant differences in baseline glucose and corticosterone levels were observed among the three groups. During restraint, hyperglycemia was observed at 10 min (p 

  • Pasireotide therapy of multiple endocrine neoplasia type 1 associated neuroendocrine tumors in female mice deleted for an men1 allele improves survival and reduces tumor progression
    Endocrinology, 2016
    Co-Authors: Gerard V Walls, Mark Stevenson, Benjamin Soukup, Kate E Lines, Ashley Grossman, Herbert A Schmid, Rajesh V Thakker
    Abstract:

    Pasireotide, a somatostatin analog, is reported to have anti-proliferative effects in neuroendocrine tumors (NETs). We therefore assessed the efficacy of Pasireotide for treating pancreatic and pituitary NETs that develop in a mouse model of multiple endocrine neoplasia type 1 (MEN1). Men1(+/-) mice were treated from age 12 mo with 40 mg/kg Pasireotide long-acting release formulation, or PBS, intramuscularly monthly for 9 mo. The Men1(+/-) mice had magnetic resonance imaging at 12 and 21 mo, and from 20 mo oral 5-bromo-2-deoxyuridine for 1 mo, to assess tumor development and proliferation, respectively. NETs were collected at age 21 mo, and proliferation and apoptosis assessed by immunohistochemistry and TUNEL assays, respectively. Pasireotide-treated Men1(+/-) mice had increased survival (Pasireotide, 80.9% vs PBS, 65.2%; P < .05), with fewer mice developing pancreatic NETs (Pasireotide, 86.9% vs PBS, 96.9%; P < .05) and smaller increases in pituitary NET volumes (pre-treated vs post-treated, 0.803 ± 0.058 mm(3) vs 2.872 ± 0.728 mm(3) [Pasireotide] compared with 0.844 ± 0.066 mm(3) vs 8.847 ±1.948 mm(3) [PBS]; P < .01). In addition, Pasireotide-treated mice had fewer pancreatic NETs compared with PBS-treated mice (2.36 ± 0.25 vs 3.72 ± 0.32, respectively; P < .001), with decreased proliferation in pancreatic NETs (Pasireotide, 0.35 ± 0.03% vs PBS, 0.78 ± 0.08%; P < .0001) and pituitary NETs (Pasireotide, 0.73 ±0.07% vs PBS, 1.81 ± 0.15%; P < .0001), but increased apoptosis in pancreatic NETs (Pasireotide, 0.42 ± 0.05% vs PBS, 0.19 ± 0.03%; P < .001) and pituitary NETs (Pasireotide, 14.75 ± 1.58% vs PBS, 2.35 ± 0.44%; P < .001). Thus, Pasireotide increased survival and inhibited pancreatic and pituitary NET growth, thereby indicating its potential as an anti-proliferative and pro-apoptotic therapy.

  • Pasireotide therapy of multiple endocrine neoplasia type 1 associated neuroendocrine tumors in female mice deleted for an men1 allele improves survival and reduces tumor progression
    Endocrinology, 2016
    Co-Authors: Gerard V Walls, Mark Stevenson, Benjamin Soukup, Kate E Lines, Ashley Grossman, Herbert A Schmid, Rajesh V Thakker
    Abstract:

    Pasireotide, a somatostatin analog, is reported to have anti-proliferative effects in neuroendocrine tumors (NETs). We therefore assessed the efficacy of Pasireotide for treating pancreatic and pituitary NETs that develop in a mouse model of multiple endocrine neoplasia type 1 (MEN1). Men1+/− mice were treated from age 12 mo with 40 mg/kg Pasireotide long-acting release formulation, or PBS, intramuscularly monthly for 9 mo. The Men1+/− mice had magnetic resonance imaging at 12 and 21 mo, and from 20 mo oral 5-bromo-2-deoxyuridine for 1 mo, to assess tumor development and proliferation, respectively. NETs were collected at age 21 mo, and proliferation and apoptosis assessed by immunohistochemistry and TUNEL assays, respectively. Pasireotide-treated Men1+/− mice had increased survival (Pasireotide, 80.9% vs PBS, 65.2%; P < .05), with fewer mice developing pancreatic NETs (Pasireotide, 86.9% vs PBS, 96.9%; P < .05) and smaller increases in pituitary NET volumes (pre-treated vs post-treated, 0.803 ± 0.058 mm3...

  • effect of Pasireotide on glucose and growth hormone related biomarkers in patients with inadequately controlled acromegaly
    Endocrine, 2016
    Co-Authors: Herbert A Schmid, Mônica R Gadelha, Ilan Shimon, Alberto M Pedroncelli, Thierry Brue, Annamaria Colao, Karen Kapur, Maria Fleseriu
    Abstract:

    The purpose of this study was to gain more insight into the mechanism of action of Pasireotide in patients who completed the PAOLA study. PAOLA was a 24-week, Phase III, randomized, three-arm study of Pasireotide LAR 40 and 60 mg versus octreotide LAR 30 mg or lanreotide Autogel 120 mg in patients with inadequately controlled acromegaly. The current work was a planned exploratory objective of the PAOLA study that evaluated changes in levels of growth hormone (GH), insulin-like growth factor 1 (IGF-1), IGF-binding proteins (IGFBP-2, IGFBP-3), glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) in each treatment arm. Responders to Pasireotide LAR (mean GH levels <2.5 μg/L and normal IGF-1 levels at 24 weeks) had lower GH and IGF-1 levels at baseline (GH 5.1 ng/mL, IGF-1 519 ng/mL) than non-responders (GH 7.9 ng/mL, IGF-1 672 ng/mL). Frequency of hyperglycaemia after Pasireotide treatment was similar in responders and non-responders and depended more on the baseline FPG level. 47 % of all patients treated with Pasireotide LAR (40 or 60 mg) did not receive antidiabetic medication at any time during this study. This is the first study to evaluate the treatment effect of Pasireotide on key hormonal and glycaemic biomarkers and to identify potential predictors of Pasireotide-associated hyperglycaemia. Pre-treatment glucose status may be predictive of the development of Pasireotide-associated hyperglycaemia. A large subset of patients with acromegaly does not experience major disturbances in glucose homeostasis while receiving Pasireotide LAR.

  • Osilodrostat (LCI699), a potent 11β-hydroxylase inhibitor, administered in combination with the multireceptor-targeted somatostatin analog Pasireotide: A 13-week study in rats.
    Toxicology and applied pharmacology, 2015
    Co-Authors: Kapil Vashisht, Herbert A Schmid, Julie Boisclair, Tsu-han Lin, William Kluwe, Heidi A. Schoenfeld, Peter Hoffmann
    Abstract:

    The somatostatin analog Pasireotide and the 11β-hydroxylase inhibitor osilodrostat (LCI699) reduce cortisol levels by distinct mechanisms of action. There exists a scientific rationale to investigate the clinical efficacy of these two agents in combination. This manuscript reports the results of a toxicology study in rats, evaluating different doses of osilodrostat and Pasireotide alone and in combination. Sixty male and 60 female rats were randomized into single-sex groups to receive daily doses of Pasireotide (0.3mg/kg/day, subcutaneously), osilodrostat (20mg/kg/day, orally), osilodrostat/Pasireotide in combination (low dose, 1.5/0.03mg/kg/day; mid-dose, 5/0.1mg/kg/day; or high dose, 20/0.3mg/kg/day), or vehicle for 13weeks. Mean body-weight gains from baseline to Week 13 were significantly lower in the Pasireotide-alone and combined-treatment groups compared to controls, and were significantly higher in female rats receiving osilodrostat monotherapy. Osilodrostat and Pasireotide monotherapies were associated with significant changes in the histology and mean weights of the pituitary and adrenal glands, liver, and ovary/oviduct. Osilodrostat alone was associated with adrenocortical hypertrophy and hepatocellular hypertrophy. In combination, osilodrostat/Pasireotide did not exacerbate any target organ changes and ameliorated the liver and adrenal gland changes observed with monotherapy. Cmax and AUC0-24h of osilodrostat and Pasireotide increased in an approximately dose-proportional manner. In conclusion, the Pasireotide and osilodrostat combination did not exacerbate changes in target organ weight or toxicity compared with either monotherapy, and had an acceptable safety profile; addition of Pasireotide to the osilodrostat regimen may attenuate potential adrenal gland hyperactivation and hepatocellular hypertrophy, which are potential side effects of osilodrostat monotherapy.

Dorte Lindqvist Hansen - One of the best experts on this subject based on the ideXlab platform.

  • postprandial hypoglycaemia after roux en y gastric bypass and the effects of acarbose sitagliptin verapamil liraglutide and Pasireotide
    Diabetes Obesity and Metabolism, 2019
    Co-Authors: Caroline C Ohrstrom, Dorte Worm, Anna Hojager, Ditte Caroline Andersen, Jens J Holst, Urd Kielgast, Dorte Lindqvist Hansen
    Abstract:

    AIM To investigate the effects of acarbose, sitagliptin, verapamil, liraglutide and Pasireotide on post-bariatric hypoglycaemia (PBH) after Roux-en-Y gastric bypass. MATERIALS AND METHODS In a randomized crossover study, 11 women who had undergone Roux-en-Y gastric bypass and had documented hypoglycaemia were each evaluated during a baseline period without treatment and during five treatment periods with the following interventions: acarbose 50 mg for 1 week, sitagliptin 100 mg for 1 week, verapamil 120 mg for 1 week, liraglutide 1.2 mg for 3 weeks and Pasireotide 300 μg as a single dose. Treatment effects were evaluated by a mixed-meal tolerance test (MMTT) and, for all treatment periods except Pasireotide, by 6 days of continuous glucose monitoring (CGM). RESULTS Treatment with acarbose and treatment with Pasireotide both significantly lifted nadir glucose levels (mean ± SEM 3.9 ± 0.2 and 7.9 ± 0.4 vs 3.4 ± 0.2; P < .03) and reduced time in hypoglycaemia during the MMTTs. Acarbose reduced peak glucose levels and time in hyperglycaemia, whereas Pasireotide greatly increased both variables. Acarbose and Pasireotide reduced insulin and C-peptide levels, and Pasireotide also diminished glucagon-like peptide-1 levels. Sitagliptin lowered nadir glucose values, while verapamil and liraglutide had no effect on hypoglycaemia. During the CGM periods, the treatments had no impact on hypoglycaemia, whereas acarbose and liraglutide reduced hyperglycaemia and glycaemic variability. CONCLUSIONS In an experimental setting, treatment with acarbose and Pasireotide reduced PBH. Acarbose appears to have an overall glucose-stabilizing effect, whereas Pasireotide leads to increased and sustained hyperglycaemia.

  • Postprandial hypoglycaemia after Roux-en-Y gastric bypass and the effects of acarbose, sitagliptin, verapamil, liraglutide and Pasireotide
    Diabetes obesity & metabolism, 2019
    Co-Authors: Caroline C Ohrstrom, Dorte Worm, Anna Hojager, Ditte Caroline Andersen, Jens J Holst, Urd Kielgast, Dorte Lindqvist Hansen
    Abstract:

    AIM To investigate the effects of acarbose, sitagliptin, verapamil, liraglutide and Pasireotide on post-bariatric hypoglycaemia (PBH) after Roux-en-Y gastric bypass. MATERIALS AND METHODS In a randomized crossover study, 11 women who had undergone Roux-en-Y gastric bypass and had documented hypoglycaemia were each evaluated during a baseline period without treatment and during five treatment periods with the following interventions: acarbose 50 mg for 1 week, sitagliptin 100 mg for 1 week, verapamil 120 mg for 1 week, liraglutide 1.2 mg for 3 weeks and Pasireotide 300 μg as a single dose. Treatment effects were evaluated by a mixed-meal tolerance test (MMTT) and, for all treatment periods except Pasireotide, by 6 days of continuous glucose monitoring (CGM). RESULTS Treatment with acarbose and treatment with Pasireotide both significantly lifted nadir glucose levels (mean ± SEM 3.9 ± 0.2 and 7.9 ± 0.4 vs 3.4 ± 0.2; P 

Yanfeng Wang - One of the best experts on this subject based on the ideXlab platform.

  • an open label dose escalation study of once daily and twice daily Pasireotide in healthy volunteers safety tolerability and effects on glucose insulin and glucagon levels
    American Journal of Therapeutics, 2014
    Co-Authors: Magdy Shenouda, Emmanuel Bouillaud, Michelle Hudson, Yanfeng Wang, Mario Maldonado, Dalal Nesheiwat
    Abstract:

    Pasireotide is a multireceptor-targeted somatostatin analogue that has high affinity for 4 of the 5 somatostatin receptor subtypes (sst1,2,3 and sst5) and has therapeutic potential in conditions with tumors of neuroendocrine origin, such as Cushing disease, acromegaly, and neuroendocrine tumors. This phase 1, open-label, dose-escalation study assessed the overall safety and tolerability of once-daily and twice-daily Pasireotide and its effects on glucose, insulin, and glucagon levels in healthy volunteers. Eleven cohorts (n = 6 for each) received subcutaneous Pasireotide 150, 300, 600, 900, 1200, or 1500 μg once daily, or 150, 300, 450, 600, or 750 μg twice daily, for 8 days. Pasireotide was generally well tolerated at all doses; adverse events were predominantly mild-to-moderate gastrointestinal disorders. All participants experienced fasting and postprandial plasma glucose elevations after all doses of Pasireotide; increases in blood glucose level seemed to be dose dependent. Hyperglycemia was associated with a marked suppression of insulin secretion and a mild inhibition of glucagon secretion. In conclusion, Pasireotide showed good overall tolerability at doses up to 1500 μg once daily and 750 μg twice daily for 8 days. Both fasting and postprandial hyperglycemia occurred after all doses of Pasireotide, which was related to the suppression of insulin secretion.

  • Assessment of the absorption, metabolism and excretion of [14C]Pasireotide in healthy volunteers using accelerator mass spectrometry
    Cancer chemotherapy and pharmacology, 2013
    Co-Authors: Tsu-han Lin, Jimmy Flarakos, M. Sharr-mcmahon, James B. Mangold, Yanfeng Wang
    Abstract:

    Pasireotide (SOM230) is a multireceptor-targeted somatostatin analog designed to have a broader somatostatin receptor binding profile than other currently available somatostatin analogs. The purpose of this study was to evaluate the absorption, metabolism and excretion of Pasireotide in healthy male subjects (N = 4) following a single, subcutaneous (sc), 600 μg dose of [14C]Pasireotide. Blood, plasma, urine and feces were collected for 240 h post-dose and analyzed for total 14C and metabolite profile by accelerator mass spectrometry (AMS) or high-performance liquid chromatography–AMS. Parent drug levels were analyzed by radioimmunoassay. [14C]Pasireotide was rapidly absorbed, with a mean peak plasma 14C concentration of 16.6 ± 5.28 ngEq/mL at 0.5 h in plasma. The parent drug to total 14C AUC0–24h ratio was 1.08, indicating that little metabolite was present in plasma up to 24 h post-dose. In pooled plasma samples (0–12 h), only unchanged [14C]Pasireotide was detected. Unchanged [14C]Pasireotide accounted for approximately 84 % of total excretion (feces and urine). Approximately 56 % of the administered radioactive dose was recovered within 240 h, eliminated primarily in feces (48.3 ± 8.16 %) and minimally in urine (7.63 ± 2.03 %). No serious adverse events were reported. A single dose of [14C]Pasireotide 600 μg sc administered to healthy male subjects was rapidly absorbed and excreted in its unchanged form primarily via the hepatic route.

  • Pasireotide som230 a novel multireceptor targeted somatostatin analogue is well tolerated when administered as a continuous 7 day subcutaneous infusion in healthy male volunteers
    The Journal of Clinical Pharmacology, 2012
    Co-Authors: Stephan Petersenn, Emmanuel Bouillaud, N Unger, Brigitte Weisshaar, Yilong Zhang, Karina Hermosillo Resendiz, Yanfeng Wang, Klaus Mann
    Abstract:

    Pasireotide is a novel multireceptor-targeted somatostatin analogue that has shown efficacy in patients with acromegaly and Cushing's disease when administered by subcutaneous (SC) injection. This study assessed the safety, tolerability, and pharmacokinetics (PK) of a continuous infusion of Pasireotide in healthy volunteers. In this single-center, open-label, dose escalation study, healthy male volunteers received a 7-day continuous SC infusion of Pasireotide in sequential ascending-dose cohorts. Single and/or 8-hour blood samples were taken on days 1 to 10 to assess PK and on days 1, 2, and 7 and a control day to assess glucose metabolism. Adverse events were evaluated throughout. Forty-four participants were enrolled into 8 cohorts: Pasireotide 450, 900, 1350, 1800 (3 cohorts were enrolled at this dose level), 2250, and 2025 µg/d. Doses were well tolerated up to 2025 µg/d. Adverse events were generally mild and gastrointestinal. Pasireotide steady-state clearance was reduced at high doses, and plasma concentrations increased disproportionately with increasing dose. Blood glucose levels increased after initiation of Pasireotide infusion with attenuation by day 7. Insulin and glucagon levels decreased after Pasireotide infusion, with insulin levels exhibiting a greater degree of suppression. Pasireotide has the potential to be administered as a long-acting release formulation, and future studies are warranted.

  • multiple once daily subcutaneous doses of Pasireotide were well tolerated in healthy male volunteers a randomized double blind placebo controlled cross over phase i study
    Endocrine, 2012
    Co-Authors: Christoph Beglinger, Y. Wang, Emmanuel Bouillaud, Christelle Darstein, Yanfeng Wang, Pharis Mohideen
    Abstract:

    A randomized, double-blind, placebo-controlled, cross-over, dose-escalating, single-center study was conducted to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of multiple once-daily (qd) subcutaneous (sc) doses of Pasireotide in healthy male subjects. Subjects received Pasireotide 50, 200, or 600 μg sc qd for 14 days and placebo in separate sequences. Thirty-three subjects were randomized. The most frequently reported drug-related adverse events were injection–site reactions (n = 18), diarrhea (n = 14) and nausea (n = 10), which were mostly mild or moderate in intensity. Pasireotide 600 μg sc was associated with pre- and post-prandial elevations in glucose levels relative to placebo; however, this effect was less pronounced on day 14 compared with day 1. PK steady state appeared to be achieved after 3 days of dosing and PK exposures had a moderate accumulation of 20–40 % across doses. Pasireotide demonstrated fast absorption (Tmax,ss: 0.25–0.5 h), low clearance (CL/Fss: 8.10–9.03 L/h), long effective half-life (T½,eff: ~12 h, on average between 9.7 and 13.1 h for 50, 200, and 600 μg sc qd), and large volume of distribution (Vz/Fss: 251–1,091 L) at steady state. Dose proportionality was confirmed for Cmax,ss; other PK parameters (Cmax, AUC0–24 h and AUCtau) were approximately dose proportional. Growth hormone inhibition was observed with Pasireotide 200 and 600 μg sc qd. Gallbladder volume increased post-prandially with Pasireotide 200 and 600 μg sc qd, which appeared to correlate with reduced levels of cholecystokinin at these doses. Pasireotide was generally well tolerated up to the tested dose of 600 μg qd, with a linear and time-independent PK profile after sc qd dosing in healthy subjects.

  • A first-in-man study to evaluate the safety, tolerability, and pharmacokinetics of Pasireotide (SOM230), a multireceptor-targeted somatostatin analog, in healthy volunteers.
    Drug design development and therapy, 2012
    Co-Authors: Georg Golor, Matthieu Ruffin, Emmanuel Bouillaud, Yanfeng Wang, Alexandra Buchelt, Mario Maldonado
    Abstract:

    Pasireotide (SOM230) is a multireceptor-targeted somatostatin analog with high binding affinity for four of the five somatostatin receptor subtypes (sst1,2,3 and sst5), and potential clinical activity in several neuroendocrine and oncologic conditions, including acromegaly, Cushing’s disease, and neuroendocrine tumors (NET). This manuscript reports the first-in-man dose-escalation study of Pasireotide, evaluating its safety, tolerability, and pharmacokinetics (PK) in healthy male volunteers. A single dose of Pasireotide 1–1200 μg was administered subcutaneously in four to eight subjects per dose level, with two additional subjects per cohort administered placebo. PK and safety evaluations were carried out over 7 days post-dose. Growth hormone (GH) suppression was evaluated using a GH-releasing hormone stimulation test on Day –1 and Day 1 at 3–5 hours post-injection. Seventy-two subjects completed the study. Pasireotide was well tolerated with no serious adverse events observed at any dose. Transient elevations in blood glucose levels were observed 2–6 hours after administration of Pasireotide at doses between 200 μg and 1200 μg, but this resolved without intervention by 23 hours post-dosing. The maximum tolerable dose was not established within the tested range. Pasireotide demonstrated a favorable PK profile with fast absorption (tmax: 0.25–0.5 hours), low clearance (CL/F: 8–13 L/hour), long effective elimination half-life (mean t½,β: 7–11 hours), and a proportional dose-exposure relationship. GH suppression of 79%–96% was observed at single Pasireotide doses between 200 μg and 1200 μg. In conclusion, Pasireotide demonstrated favorable safety, tolerability, and PK profiles, as well as promising activity in suppressing the release of GH. The efficacy and safety of Pasireotide is currently being evaluated in patients with acromegaly, Cushing’s disease, NET, and various non-neuroendocrine disorders.

Emmanuel Bouillaud - One of the best experts on this subject based on the ideXlab platform.

  • an open label dose escalation study of once daily and twice daily Pasireotide in healthy volunteers safety tolerability and effects on glucose insulin and glucagon levels
    American Journal of Therapeutics, 2014
    Co-Authors: Magdy Shenouda, Emmanuel Bouillaud, Michelle Hudson, Yanfeng Wang, Mario Maldonado, Dalal Nesheiwat
    Abstract:

    Pasireotide is a multireceptor-targeted somatostatin analogue that has high affinity for 4 of the 5 somatostatin receptor subtypes (sst1,2,3 and sst5) and has therapeutic potential in conditions with tumors of neuroendocrine origin, such as Cushing disease, acromegaly, and neuroendocrine tumors. This phase 1, open-label, dose-escalation study assessed the overall safety and tolerability of once-daily and twice-daily Pasireotide and its effects on glucose, insulin, and glucagon levels in healthy volunteers. Eleven cohorts (n = 6 for each) received subcutaneous Pasireotide 150, 300, 600, 900, 1200, or 1500 μg once daily, or 150, 300, 450, 600, or 750 μg twice daily, for 8 days. Pasireotide was generally well tolerated at all doses; adverse events were predominantly mild-to-moderate gastrointestinal disorders. All participants experienced fasting and postprandial plasma glucose elevations after all doses of Pasireotide; increases in blood glucose level seemed to be dose dependent. Hyperglycemia was associated with a marked suppression of insulin secretion and a mild inhibition of glucagon secretion. In conclusion, Pasireotide showed good overall tolerability at doses up to 1500 μg once daily and 750 μg twice daily for 8 days. Both fasting and postprandial hyperglycemia occurred after all doses of Pasireotide, which was related to the suppression of insulin secretion.

  • Pasireotide som230 a novel multireceptor targeted somatostatin analogue is well tolerated when administered as a continuous 7 day subcutaneous infusion in healthy male volunteers
    The Journal of Clinical Pharmacology, 2012
    Co-Authors: Stephan Petersenn, Emmanuel Bouillaud, N Unger, Brigitte Weisshaar, Yilong Zhang, Karina Hermosillo Resendiz, Yanfeng Wang, Klaus Mann
    Abstract:

    Pasireotide is a novel multireceptor-targeted somatostatin analogue that has shown efficacy in patients with acromegaly and Cushing's disease when administered by subcutaneous (SC) injection. This study assessed the safety, tolerability, and pharmacokinetics (PK) of a continuous infusion of Pasireotide in healthy volunteers. In this single-center, open-label, dose escalation study, healthy male volunteers received a 7-day continuous SC infusion of Pasireotide in sequential ascending-dose cohorts. Single and/or 8-hour blood samples were taken on days 1 to 10 to assess PK and on days 1, 2, and 7 and a control day to assess glucose metabolism. Adverse events were evaluated throughout. Forty-four participants were enrolled into 8 cohorts: Pasireotide 450, 900, 1350, 1800 (3 cohorts were enrolled at this dose level), 2250, and 2025 µg/d. Doses were well tolerated up to 2025 µg/d. Adverse events were generally mild and gastrointestinal. Pasireotide steady-state clearance was reduced at high doses, and plasma concentrations increased disproportionately with increasing dose. Blood glucose levels increased after initiation of Pasireotide infusion with attenuation by day 7. Insulin and glucagon levels decreased after Pasireotide infusion, with insulin levels exhibiting a greater degree of suppression. Pasireotide has the potential to be administered as a long-acting release formulation, and future studies are warranted.

  • multiple once daily subcutaneous doses of Pasireotide were well tolerated in healthy male volunteers a randomized double blind placebo controlled cross over phase i study
    Endocrine, 2012
    Co-Authors: Christoph Beglinger, Y. Wang, Emmanuel Bouillaud, Christelle Darstein, Yanfeng Wang, Pharis Mohideen
    Abstract:

    A randomized, double-blind, placebo-controlled, cross-over, dose-escalating, single-center study was conducted to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of multiple once-daily (qd) subcutaneous (sc) doses of Pasireotide in healthy male subjects. Subjects received Pasireotide 50, 200, or 600 μg sc qd for 14 days and placebo in separate sequences. Thirty-three subjects were randomized. The most frequently reported drug-related adverse events were injection–site reactions (n = 18), diarrhea (n = 14) and nausea (n = 10), which were mostly mild or moderate in intensity. Pasireotide 600 μg sc was associated with pre- and post-prandial elevations in glucose levels relative to placebo; however, this effect was less pronounced on day 14 compared with day 1. PK steady state appeared to be achieved after 3 days of dosing and PK exposures had a moderate accumulation of 20–40 % across doses. Pasireotide demonstrated fast absorption (Tmax,ss: 0.25–0.5 h), low clearance (CL/Fss: 8.10–9.03 L/h), long effective half-life (T½,eff: ~12 h, on average between 9.7 and 13.1 h for 50, 200, and 600 μg sc qd), and large volume of distribution (Vz/Fss: 251–1,091 L) at steady state. Dose proportionality was confirmed for Cmax,ss; other PK parameters (Cmax, AUC0–24 h and AUCtau) were approximately dose proportional. Growth hormone inhibition was observed with Pasireotide 200 and 600 μg sc qd. Gallbladder volume increased post-prandially with Pasireotide 200 and 600 μg sc qd, which appeared to correlate with reduced levels of cholecystokinin at these doses. Pasireotide was generally well tolerated up to the tested dose of 600 μg qd, with a linear and time-independent PK profile after sc qd dosing in healthy subjects.

  • A first-in-man study to evaluate the safety, tolerability, and pharmacokinetics of Pasireotide (SOM230), a multireceptor-targeted somatostatin analog, in healthy volunteers.
    Drug design development and therapy, 2012
    Co-Authors: Georg Golor, Matthieu Ruffin, Emmanuel Bouillaud, Yanfeng Wang, Alexandra Buchelt, Mario Maldonado
    Abstract:

    Pasireotide (SOM230) is a multireceptor-targeted somatostatin analog with high binding affinity for four of the five somatostatin receptor subtypes (sst1,2,3 and sst5), and potential clinical activity in several neuroendocrine and oncologic conditions, including acromegaly, Cushing’s disease, and neuroendocrine tumors (NET). This manuscript reports the first-in-man dose-escalation study of Pasireotide, evaluating its safety, tolerability, and pharmacokinetics (PK) in healthy male volunteers. A single dose of Pasireotide 1–1200 μg was administered subcutaneously in four to eight subjects per dose level, with two additional subjects per cohort administered placebo. PK and safety evaluations were carried out over 7 days post-dose. Growth hormone (GH) suppression was evaluated using a GH-releasing hormone stimulation test on Day –1 and Day 1 at 3–5 hours post-injection. Seventy-two subjects completed the study. Pasireotide was well tolerated with no serious adverse events observed at any dose. Transient elevations in blood glucose levels were observed 2–6 hours after administration of Pasireotide at doses between 200 μg and 1200 μg, but this resolved without intervention by 23 hours post-dosing. The maximum tolerable dose was not established within the tested range. Pasireotide demonstrated a favorable PK profile with fast absorption (tmax: 0.25–0.5 hours), low clearance (CL/F: 8–13 L/hour), long effective elimination half-life (mean t½,β: 7–11 hours), and a proportional dose-exposure relationship. GH suppression of 79%–96% was observed at single Pasireotide doses between 200 μg and 1200 μg. In conclusion, Pasireotide demonstrated favorable safety, tolerability, and PK profiles, as well as promising activity in suppressing the release of GH. The efficacy and safety of Pasireotide is currently being evaluated in patients with acromegaly, Cushing’s disease, NET, and various non-neuroendocrine disorders.

  • Safety, tolerability, and pharmacokinetics of a single dose of Pasireotide long-acting release in healthy volunteers: a single-center Phase I study
    European journal of endocrinology, 2012
    Co-Authors: Hartmut Dietrich, Matthieu Ruffin, Dongweon Song, Emmanuel Bouillaud, Yanfeng Wang, Jens Hasskarl
    Abstract:

    Objective: This study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PKs) of different doses of a long-acting release (LAR) formulation of Pasireotide in healthy subjects. Design: Single-center, open-label, randomized Phase I study. Methods: Twelve healthy male subjects received a single s.c. dose of Pasireotide 300 mg followed by a washout period of 7 days (or at least 5 days), before receiving an i.m. injection of Pasireotide -LAR 40 mg (nZ5) or 60 mg (nZ7). Assessments included adverse events (AEs), PKs, and glucose, insulin, glucagon, and HbA1c levels. Results: Pasireotide LAR showed an extended-release profile over 1 month with two concentration peaks observed 1 and around 20 days after injection. The area under curve exposure of Pasireotide LAR was dose proportional when the dose levels were compared, and the bioavailability of the LAR relative to the s.c. formulation was complete. Administration of Pasireotide LAR resulted in an increase in fasting and postprandial glucose levels; however, an attenuation of the hyperglycemic effect was observed after 15 days. The most frequently reported AEs were mild-to-moderate diarrhea, abdominal pain, and flatulence. Only gastrointestinal AEs and injection site reactions were suspected to be drug related. Conclusions: Pasireotide LAR was generally well tolerated with mostly mild AEs at doses up to 60 mg and showed a dose-proportional, extended-release profile in healthy subjects. Based on the favorable results of this study, further clinical development of Pasireotide LAR is under way, which will give insight into the PKs, efficacy, and safety of Pasireotide LAR in patient populations.

Maria Fleseriu - One of the best experts on this subject based on the ideXlab platform.

  • Pasireotide for acromegaly long term outcomes from an extension to the phase iii paola study
    European Journal of Endocrinology, 2020
    Co-Authors: Annamaria Colao, Marcello D Bronstein, Maria Fleseriu, Ilan Shimon, Thierry Brue, Laura De Marinis, Mirtha Guitelman, Gérald Raverot, Jürgen Fleck, Pritam Gupta
    Abstract:

    Objective In the Phase III PAOLA study (clinicaltrials.gov: NCT01137682), enrolled patients had uncontrolled acromegaly despite ≥6 months of octreotide/lanreotide treatment before study start. More patients achieved biochemical control with long-acting Pasireotide versus continued treatment with octreotide/lanreotide (active control) at month 6. The current work assessed the extent of comorbidities at baseline and outcomes during a long-term extension. Design/methods Patients receiving Pasireotide 40 or 60 mg at core study end could continue on the same dose in an extension phase if biochemically controlled or receive Pasireotide 60 mg if uncontrolled. Uncontrolled patients on active control were switched to Pasireotide 40 mg, with the dose increased at week 16 of the extension if still uncontrolled (crossover group). Efficacy and safety are reported to 304 weeks (~5.8 years) for patients randomized to Pasireotide (core + extension), and 268 weeks for patients in the crossover group (extension only). Results Almost half (49.5%; 98/198) of patients had ≥3 comorbidities at core baseline. During the extension, 173 patients received Pasireotide. Pasireotide effectively and consistently reduced GH and IGF-I levels for up to 5.8 years' treatment; 37.0% of patients achieved GH <1.0 µg/L and normal IGF-I at some point during the core or extension. Improvements were observed in key symptoms. The long-term safety profile was similar to that in the core study; 23/173 patients discontinued treatment because of adverse events. Conclusions In this patient population with a high burden of comorbid illness, Pasireotide was well tolerated and efficacious, providing prolonged maintenance of biochemical control and improving symptoms.

  • Risk factors and management of Pasireotide-associated hyperglycemia in acromegaly
    Endocrine Connections, 2020
    Co-Authors: Mônica R Gadelha, Aart J. Van Der Lely, Marcello D Bronstein, Thierry C Brue, Maria Fleseriu, Ilan Shimon, Shoba Ravichandran, Albert Kandra, Alberto M Pedroncelli
    Abstract:

    Pasireotide, a multireceptor-targeted somatostatin analog with highest affinity for somatostatin receptor subtype (SST) 5, has demonstrated superior efficacy over the SST2-preferential somatostatin analogs octreotide and lanreotide. The safety profile is similar to those of octreotide and lanreotide, except for a higher frequency and degree of hyperglycemia. This analysis investigated baseline characteristics and occurrence and management of hyperglycemia during Pasireotide treatment in patients with acromegaly treated in two prospective clinical studies, SOM230C2305 (C2305) and SOM230C2402 (C2402; PAOLA). One hundred and seventy-eight patients naïve to medical therapy at baseline (C2305) and 125 uncontrolled on first-generation somatostatin analogs at baseline (C2402) received long-acting Pasireotide in these studies. Of patients treated with Pasireotide in studies C2305 and C2402, respectively, 75.3 (134/178) and 65.6% (82/125) developed hyperglycemia or experienced worsening of existing hyperglycemia. Occurrence of hyperglycemia during Pasireotide treatment was less frequent in patients with lower age (<40 years, C2402; <30 years, C2305), normal glucose tolerance, and no history of hypertension or dyslipidemia at baseline. Thirteen (4%) patients discontinued Pasireotide because of hyperglycemia-related adverse events. Metformin alone or in combination with other oral antidiabetic medications controlled elevations in glucose levels in most Pasireotide-treated patients; 78% of C2305 patients and 73 (Pasireotide 40 mg) and 60% (Pasireotide 60 mg) of C2402 patients achieved the ADA/EASD goal of HbA1c <7% (<53 mmol/mol) at the end of the core phase. Not all patients develop hyperglycemia, and it is reversible upon Pasireotide withdrawal. Close monitoring, patient education and prompt action remain key elements in addressing hyperglycemia during Pasireotide treatment.

  • Pasireotide for acromegaly: long-term outcomes from an extension to the Phase III PAOLA study
    European journal of endocrinology, 2020
    Co-Authors: Annamaria Colao, Marcello D Bronstein, Maria Fleseriu, Ilan Shimon, Thierry Brue, Laura De Marinis, Mirtha Guitelman, Gérald Raverot, Jürgen Fleck, Pritam Gupta
    Abstract:

    Objective In the Phase III PAOLA study (clinicaltrials.gov: NCT01137682), enrolled patients had uncontrolled acromegaly despite ≥6 months of octreotide/lanreotide treatment before study start. More patients achieved biochemical control with long-acting Pasireotide versus continued treatment with octreotide/lanreotide (active control) at month 6. The current work assessed the extent of comorbidities at baseline and outcomes during a long-term extension. Design/methods Patients receiving Pasireotide 40 or 60 mg at core study end could continue on the same dose in an extension phase if biochemically controlled or receive Pasireotide 60 mg if uncontrolled. Uncontrolled patients on active control were switched to Pasireotide 40 mg, with the dose increased at week 16 of the extension if still uncontrolled (crossover group). Efficacy and safety are reported to 304 weeks (~5.8 years) for patients randomized to Pasireotide (core + extension), and 268 weeks for patients in the crossover group (extension only). Results Almost half (49.5%; 98/198) of patients had ≥3 comorbidities at core baseline. During the extension, 173 patients received Pasireotide. Pasireotide effectively and consistently reduced GH and IGF-I levels for up to 5.8 years' treatment; 37.0% of patients achieved GH

  • Medical Therapy with Pasireotide in Recurrent Cushing's Disease: Experience of Patients Treated for At Least 1 Year at a Single Center.
    Frontiers in endocrinology, 2017
    Co-Authors: Chris G. Yedinak, Sarah Hopkins, Jessica Williams, Aly Ibrahim, Justin S. Cetas, Maria Fleseriu
    Abstract:

    Subcutaneous (SC) injection of Pasireotide, a somatostatin analog, is approved for the treatment of adults with Cushing’s disease (CD) for whom pituitary surgery was unsuccessful or is not an option. We highlight the symptomatic and biochemical improvement of 6 patients with recurrent CD treated with Pasireotide SC at a single center for at least 1 year. Patients were treated either through commercial use (n=5) or through the Phase 3 trial (n=1; ClinicalTrials.gov identifier, NCT00434148; study number, B2305). Most patients (n=5) were female, and the mean age at diagnosis was 35.8 years. All patients demonstrated biochemical control at 1 year of treatment. Three of the 5 real-world patients followed for more than 1 year remain on Pasireotide SC, and are controlled. Two patients discontinued Pasireotide SC; 1 patient because of persistently elevated urinary free cortisol levels and gallstones, and the other because of treatment for an unrelated brain tumor. Symptomatic improvement varied, but all patients demonstrated weight loss. Nausea and mild, transient injection-site reactions were the most frequently reported adverse events. Although glycated hemoglobin (HbA1c) increased after treatment initiation, 4 of 5 patients maintained HbA1c levels ≤7.0% while receiving Pasireotide SC and concomitant individualized diabetes medication, if necessary. In patients who discontinued Pasireotide SC, HbA1c levels decreased within 6 weeks. This report documents real-world use of Pasireotide SC and indicates its effectiveness as a long-term treatment option for patients with CD. Although hyperglycemia was observed in most patients, it was managed with appropriate monitoring and treatment and was reversible upon discontinuation of Pasireotide SC.

  • safety and tolerability of Pasireotide long acting release in acromegaly results from the acromegaly open label multicenter safety monitoring program for treating patients who have a need to receive medical therapy access study
    Endocrine, 2017
    Co-Authors: Maria Fleseriu, Elisha S Rusch, Eliza B Geer
    Abstract:

    Purpose Pasireotide long-acting release is a somatostatin analog that is indicated for treatment of patients with acromegaly. This analysis documents the safety of Pasireotide long-acting release in patients with acromegaly enrolled in the ACCESS trial (ClinicalTrials.gov identifier: NCT01995734).