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Publications (19)57.49 Total impact

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    ABSTRACT: We evaluated the drug-drug interaction between pasireotide SC and verapamil, a known P-glycoprotein inhibitor. Subjects received pasireotide SC (single dose, 600 μg) on day 1, and samples for pharmacokinetics evaluation were collected from days 1 to 8. Subjects received an oral dose of verapamil 240 mg/d for 10 days (days 15–24). On day 18, subjects also received pasireotide SC 600 μg. Pharmacokinetic sampling for pasireotide SC and verapamil was done during days 18 to 25 and days 15 to 21, respectively. Safety evaluations were performed throughout the study period, including a 30-day post-treatment follow-up. Pharmacokinetic profiles of pasireotide SC alone and in combination with verapamil sustained-release (SR) were super-imposable with the geometric mean ratios (90% confidence interval [CI]) of 0.98 (0.91–1.06) for Cmax, 0.97 (0.90–1.04) for AUClast, and 0.98 (0.92–1.05) for AUCinf. Exploratory analyses showed a 17% (90% CI, 0.72–0.94) reduction in Ctrough and 31% (0.58–0.82) reduction in Cmax (8 h post-dose) for verapamil SR with pasireotide SC versus verapamil alone. Pasireotide SC with or without verapamil was well tolerated. In conclusion, there was no change in the rate of pasireotide absorption and elimination or extent of exposure following concomitant administration with verapamil.
    The Journal of Clinical Pharmacology 05/2014; · 2.84 Impact Factor
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    ABSTRACT: Pasireotide, a multireceptor-targeted somatostatin analogue, has exhibited favourable 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 (20mg group); 6.42, 6.62 and 7.12 (40mg group); and 9.51, 11.7 and 13.0 (60mg group). At study end, 51% and 57% of patients achieved GH levels ≤2.5μg/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.
    The Journal of Clinical Pharmacology 05/2014; · 2.84 Impact Factor
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    ABSTRACT: Purpose The purpose of this study was to assess the pharmacokinetic (PK) properties and safety of single and multiple doses of subcutaneous (SC) pasireotide and a single-dose intramuscular (IM) long-acting release (LAR) formulation of pasireotide in Chinese healthy volunteers (HVs) versus the PK properties in Western HVs (pooled from previous PK studies). Methods In this phase I, single-center, open-label study, 45 Chinese male HVs were evenly randomized to 1 to 9 treatment sequences: each volunteer received a single dose of 300, 600, or 900 μg of pasireotide SC on day 1, followed by administration of the same dose BID from day 15 to the morning of day 19, and then a single IM dose of 20, 40, or 60 mg of pasireotide LAR on day 33. The PK parameters were assessed with noncompartmental analysis. Statistical comparison of PK parameters, including AUC, Cmax, and CL/F from both formulations, was made for Chinese versus Western male HVs. The safety profile was also assessed. Metabolic parameters, including blood glucose, insulin, and glucagon, and measures that reflect the effects of pasireotide LAR on relatively long-term glucose control, lipid metabolism, and systemic concentrations of pancreatic enzymes and thyrotropin were evaluated. Findings Of the 45 randomized HVs, 42 completed the study per protocol, 1 withdrew his informed consent for personal reasons, and 2 prematurely discontinued the study because of adverse events (AEs). Concentration-time and safety profiles of both formulations were similar to those reported in Western HVs. Mean geometric mean ratios (GMRs) of Chinese versus Western HVs ranged from 0.79 to 1.42. For most primary PK parameters, 90% CIs for GMRs were within a predefined ethnic insensitivity interval (90% CI, 0.70–1.43). After considering age and weight as covariates in the statistical model, the GMRs and 90% CIs for other PK parameters were within the predefined interval (Cmax in single-dose SC administration) or significantly decreased (Cmin,ss in multiple BID SC doses and first peak Cmax in the single-dose LAR formulation). No serious AEs were reported. Both formulations were well tolerated; pasireotide SC caused transient changes in glucose metabolism. Owing to the differential binding affinity to the somatostatin receptor subtypes, pasireotide LAR elicited a concentration-dependent increase of fasting blood glucose, substantial reduction in triglyceride, and a mild decrease in cholesterol. The most frequently reported AEs after single-dose and multiple-dose pasireotide SC were injection site reaction, nausea, dizziness, and diarrhea; most HVs developed diarrhea with single-dose pasireotide LAR. Implications The pasireotide formulations had similar PK and safety profiles between Chinese and Western male HVs. Thus, no ethnic sensitivity was found for pasireotide SC or LAR.
    Clinical Therapeutics. 01/2014;
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    ABSTRACT: The aim of this study was to evaluate the effects of subcutaneous pasireotide on cardiac repolarization in healthy volunteers. Healthy volunteers were randomized to one of four treatment sequences (n = 112) involving four successive treatments in different order: pasireotide 600 µg (therapeutic dose) or 1,950 µg (maximum tolerated dose) bid by subcutaneous injection (sc), placebo injection and oral moxifloxacin. Maximum ΔΔQTcI occurred 2 hours post-dose for both doses of pasireotide. Mean ΔΔQTcI was 13.2 milliseconds (90% CI: 11.4, 15.0) and 16.1 milliseconds (90% CI: 14.3, 17.9) for the 600 and 1,950 µg bid doses, respectively. Maximal placebo-subtracted change in QTcI from baseline for moxifloxacin was 11.1 (90% CI: 9.3, 12.9) milliseconds. Both pasireotide doses caused a reduction in heart rate: maximal heart rate change compared with placebo occurred at 1 hour for pasireotide 600 µg bid and at 0.5 hours for pasireotide 1,950 µg bid, with heart rate reductions of 10.4 and 14.9 bpm, respectively. At the therapeutic dose of 600 µg, pasireotide has a modest QT-prolonging effect. The relatively small increase of ∼3 milliseconds in ΔΔQTcI in the presence of a 3.25-fold increase in dose suggests a relatively flat dose-effect relationship of pasireotide on ΔΔQTcI in healthy volunteers. No safety concerns for pasireotide were identified during the study.
    The Journal of Clinical Pharmacology 10/2013; · 2.84 Impact Factor
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    ABSTRACT: In a previous 15-day, Phase II study of patients with de novo or persistent/recurrent Cushing's disease (core study), treatment with pasireotide 600 μg sc bid reduced urinary free cortisol (UFC) levels in 76 % of patients and normalized UFC in 17 %. The objective of this study was to evaluate the efficacy and safety of extended treatment with pasireotide. This was a planned, open-ended, single-arm, multicenter extension study (primary endpoint: 6 months). Patients aged ≥18 years with Cushing's disease who completed the core study could enter the extension if they achieved UFC normalization at core study end and/or obtained significant clinical benefit. Of the 38 patients who completed the core study, 19 entered the extension and 18 were included in the efficacy analyses (three responders, 11 reducers, four non-reducers in the core study). At data cut-off, median treatment duration in the extension was 9.7 months (range: 2 months to 4.8 years). At extension month 6, 56 % of the 18 patients had lower UFC than at core baseline and 22 % had normalized UFC. Of the four patients who remained on study drug at month 24, one had normalized UFC. Reductions in serum cortisol, plasma adrenocorticotropic hormone, body weight and diastolic blood pressure were observed. The most common adverse events were mild-to-moderate gastrointestinal disorders and hyperglycemia. Pasireotide offers a tumor-directed medical therapy that may be effective for the extended treatment of some patients with Cushing's disease.
    Pituitary 08/2013; · 2.67 Impact Factor
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    ABSTRACT: PURPOSE: Pasireotide (SOM230), a novel multireceptor ligand somatostatin analog (SSA), binds with high affinity to four of the five somatostatin receptor subtypes (sst1-3, 5). This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics profiles of pasireotide long-acting release (LAR) formulation in patients with advanced gastroenteropancreatic neuroendocrine tumor (GEP NET) refractory to other SSAs. METHODS: In this randomized, multicenter, open-label, phase II study, patients with biopsy-proven primary or metastatic GEP NET refractory to available SSAs were randomly assigned 1:1:1 to receive pasireotide LAR by deep intragluteal injection at a dose of 20, 40, or 60 mg once every 28 days for 3 months. RESULTS: Forty-two patients received pasireotide LAR. Adverse events were reported by 34 (81 %) patients, with the most frequently reported including diarrhea, fatigue, abdominal pain, and nausea. Mean fasting glucose levels were increased compared with baseline at all points throughout the study. After the third injection of pasireotide LAR, the median trough plasma concentrations on day 84 were 4.82, 12.0, and 19.7 ng/mL in the 20-, 40-, and 60-mg treatment groups, respectively. Drug accumulation was limited for each dose based on the increase in trough concentrations after the first to third injections (accumulation ratios were approximately 1 from all dose levels). CONCLUSIONS: This study demonstrated that a new, once-monthly, intramuscular LAR formulation of pasireotide was well tolerated in patients with advanced GEP NET. Steady state levels of plasma pasireotide were achieved after three injections.
    Cancer Chemotherapy and Pharmacology 06/2013; · 2.80 Impact Factor
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    Pituitary 05/2013; · 2.67 Impact Factor
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    ABSTRACT: Pasireotide has a broader somatostatin receptor binding profile than other somatostatin analogues. A 16-week, Phase II trial showed that pasireotide may be an effective treatment for acromegaly. An extension to this trial assessed the long-term efficacy and safety of pasireotide. This study was an open-label, single-arm, open-ended extension study (primary efficacy and safety evaluated at month 6). Patients could enter the extension if they achieved biochemical control (GH ≤ 2.5 μg/L and normal IGF-1) or showed clinically relevant improvements during the core study. Thirty of the 60 patients who received pasireotide (200-900 μg bid) in the core study entered the extension. At extension month 6, of the 26 evaluable patients, six were biochemically controlled, of whom five had achieved control during the core study. Normal IGF-1 was achieved by 13/26 patients and GH ≤ 2.5 μg/L by 12/26 at month 6. Nine patients received pasireotide for ≥24 months in the extension; three who were biochemically controlled at month 24 had achieved control during the core study. Of 29 patients with MRI data, nine had significant (≥20 %) tumor volume reduction during the core study; an additional eight had significant reduction during the extension. The most common adverse events were transient gastrointestinal disturbances; hyperglycemia-related events occurred in 14 patients. Twenty patients had fasting plasma glucose shifted to a higher category during the extension. However, last available glucose measurements were normal for 17 patients. Pasireotide has the potential to be an effective, long-term medical treatment for acromegaly, providing sustained biochemical control and significant reductions in tumor volume.
    Pituitary 03/2013; · 2.67 Impact Factor
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    ABSTRACT: Aims Pasireotide, a multireceptor-targeted somatostatin analogue with efficacy in Cushing's disease and acromegaly, can affect glucose metabolism due to inhibition of insulin secretion and incretin hormone responses. A study was therefore conducted to evaluate different antihyperglycemic drugs in the management of pasireotide-associated hyperglycemia. Methods This was a 1-week, Phase I, open-label study. Healthy male volunteers were randomized to pasireotide 600 μg sc bid alone or co-administered with metformin 500 mg po bid, nateglinide 60 mg po tid, vildagliptin 50 mg po bid, or liraglutide 0.6 mg sc qd. An oral glucose tolerance test (OGTT) was performed on days 1 and 7 to evaluate effects on serum insulin, plasma glucose and glucagon levels. Safety/tolerability and pharmacokinetic effects were also evaluated. Results Ninety healthy male volunteers were enrolled (n = 18 per arm). After 7 days of treatment, plasma glucose AUC post-OGTT increased by 69% with pasireotide alone. The effect was reduced by 13%, 29%, 45% and 72% with co-administration of metformin, nateglinide, vildagliptin and liraglutide, respectively. On day 7, compared with pasireotide alone, the decrease in serum insulin was attenuated with nateglinide, metformin, liraglutide and vildagliptin co-administration (levels were 3%, 6%, 34% and 71% higher, respectively). Minimal changes in plasma glucagon were observed. Adverse events were consistent with the safety profiles of the drugs used. Conclusions Vildagliptin and liraglutide were most effective in minimizing pasireotide-associated hyperglycemia in healthy volunteers.
    Diabetes research and clinical practice 01/2013; · 2.74 Impact Factor
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    ABSTRACT: Pasireotide (SOM230) is a novel multireceptor-targeted somatostatin (sst) analog with high binding affinity for sst receptor subtype 1, 2, 3 (sst(1,2,3)) and sst(5). Because of this binding profile, pasireotide may offer symptom control in patients with neuroendocrine tumors (NETs) and carcinoid syndrome no longer responsive to octreotide LAR. This was a phase II, open-label, multicenter study of pasireotide in patients with advanced NET whose symptoms of carcinoid syndrome (diarrhea/flushing) were inadequately controlled by octreotide LAR. Patients received s.c. pasireotide 150 μg twice daily (bid), escalated to a maximum dose of 1200 μg bid until a clinical response was achieved. Forty-four patients were evaluated for efficacy and 45 for tolerability. Pasireotide 600-900 μg s.c. bid effectively controlled the symptoms of diarrhea and flushing in 27% of patients. Evaluation of tumor response in 23 patients showed 13 with stable disease and ten with progressive disease at study end. The most common drug-related adverse events were nausea (27%), abdominal pain (20%), weight loss (20%), and hyperglycemia (16%) and most were of mild or moderate severity. Pasireotide 600-900 μg s.c. bid was effective and generally well tolerated in controlling the symptoms of carcinoid syndrome in 27% of patients with advanced NET refractory or resistant to octreotide LAR therapy.
    Endocrine Related Cancer 07/2012; 19(5):657-666. · 5.26 Impact Factor
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    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.
    American journal of therapeutics 06/2012; · 1.29 Impact Factor
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    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 (T (max,ss): 0.25-0.5 h), low clearance (CL/F (ss): 8.10-9.03 L/h), long effective half-life (T (½,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 (V (z)/F (ss): 251-1,091 L) at steady state. Dose proportionality was confirmed for C (max,ss); other PK parameters (C (max), AUC(0-24 h) and AUC(tau)) 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.
    Endocrine 04/2012; 42(2):366-74. · 1.42 Impact Factor
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    ABSTRACT: 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. Single-center, open-label, randomized Phase I study. Twelve healthy male subjects received a single s.c. dose of pasireotide 300 μg followed by a washout period of 7 days (or at least 5 days), before receiving an i.m. injection of pasireotide -LAR 40 mg (n=5) or 60 mg (n=7). Assessments included adverse events (AEs), PKs, and glucose, insulin, glucagon, and HbA1c levels. 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. 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.
    European Journal of Endocrinology 03/2012; 166(5):821-8. · 3.14 Impact Factor
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    ABSTRACT: Pasireotide is a multireceptor-targeted somatostatin analogue with high binding affinity for somatostatin receptor subtypes SST 1, 2, 3, and 5. To evaluate the safety profile, tolerability, and pharmacokinetic profile of pasireotide in single- and divided-dose regimens in healthy volunteers. A single-center, open-label, ascending-dose study was performed in healthy volunteers. Pasireotide, 900, 1200, and 1500 μg SC, was administered as either a single dose or as two divided doses given 12 hours apart, with a 7-day washout period between treatments. Seventeen men (median age, 26 years) were enrolled. Their median weight was 81 kg, and 65% were white. One participant dropped out because of a grade 2 adverse event; most other adverse events were mild and affected the gastrointestinal tract. Blood glucose concentration increased after pasireotide administration, but returned to normal within 10 hours. After single-dose administration, pasireotide plasma concentration peaked rapidly at 15 minutes to 1 hour after dosing, followed by a tri-exponential (α, β, and γ phases) decline over time. Mean t(½) values during the α, β, and γ phases were approximately 2 to 3, 12 to 17, and 54 to 97 hours, respectively. In the single-dose cohort, the mean (SD) AUC(∞) was 110 (29), 149 (42), and 188 (52) h · ng/mL in the 900-, 1200-, and 1500-μg groups, respectively. Time to reach C(max) was 0.69 (0.41), 0.59 (0.38), and 0.56 (0.18) hours in the 900-, 1200-, and 1500-μg groups, respectively. AUC(∞) values were similar in the single-dose and divided-dose cohorts. Mean total body clearance was 8 to 9 L/h across the dosage groups and dosing regimens, indicating a linear pharmacokinetic profile between doses. When administered as a single- or divided-dose regimen, pasireotide had a favorable tolerability profile in this selected group of healthy male volunteers. Its pharmacokinetic profile indicated rapid absorption, low clearance, high volume of distribution, and a long terminal half-life.
    Clinical Therapeutics 02/2012; 34(3):677-88. · 2.23 Impact Factor
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    ABSTRACT: Pasireotide is a novel, multireceptor-targeted somatostatin analogue with high affinity for sst(1,2,3) and sst(5) under clinical evaluation in tumors of neuroendocrine origin, including Cushing's disease, acromegaly, and neuroendocrine tumors. In this phase I, open-label, multicenter study, the pharmacokinetics and safety of a single subcutaneous (SC) injection of pasireotide 600 µg were evaluated in adults with normal hepatic function (n = 15) and mild (n = 6), moderate (n = 7), or severe hepatic impairment (n = 6). Following a single dose of pasireotide SC 600 µg, there were no significant differences in the plasma exposure of pasireotide between participants with normal hepatic function or mild hepatic impairment. Subjects with moderate and severe hepatic impairment showed an increase in AUC(∞) by 56% and 42%, respectively; this increase was 60% and 79% respectively, after adjusting for differences in age, BMI, and baseline serum albumin level between treatment groups. The incidence and severity of adverse events were similar across cohorts, with no clinically relevant differences in type or frequency of adverse events between cohorts. In conclusion, a single dose of pasireotide SC 600 µg was well tolerated in subjects with hepatic impairment. Drug exposure in subjects with mild hepatic impairment was similar to that seen in healthy volunteers, whereas subjects with moderate and severe hepatic impairment experienced higher exposure to pasireotide. Adjustment of the pasireotide dose may be required for patients with moderate and severe hepatic impairment.
    The Journal of Clinical Pharmacology 01/2012; 52(4):552-8. · 2.84 Impact Factor
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    ABSTRACT: Pasireotide (SOM230) is a multireceptor-targeted somatostatin analog with high binding affinity for four of the five somatostatin receptor subtypes (sst(1,2,3) and sst(5)), 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 (t(max): 0.25-0.5 hours), low clearance (CL/F: 8-13 L/hour), long effective elimination half-life (mean t(½,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.
    Drug Design, Development and Therapy 01/2012; 6:71-9. · 3.49 Impact Factor
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    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.
    The Journal of Clinical Pharmacology 06/2011; 52(7):1017-27. · 2.84 Impact Factor
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    ABSTRACT: Pasireotide (SOM230) is a novel multireceptor ligand somatostatin analog with affinity for somatostatin receptor subtypes sst(1-3) and sst(5). Because most GH-secreting pituitary adenomas express sst(2) and sst(5), pasireotide has the potential to be more effective than the sst(2)-preferential somatostatin analogs octreotide and lanreotide. Our objective was to evaluate the efficacy and safety of three different doses of pasireotide in patients with acromegaly. We conducted a phase II, randomized, multicenter, open-label, three-way, crossover study. Sixty patients with acromegaly, defined by a 2-h five-point mean GH level higher than 5 microg/liter, lack of suppression of GH to less than 1 microg/liter after oral glucose tolerance test, and elevated IGF-I for age- and sex-matched controls. Patients could have had previous surgery, radiotherapy, and/or medical therapy or no previous treatment. After treatment with octreotide 100 microg s.c. three times daily for 28 d, each patient received pasireotide 200, 400, and 600 microg s.c. twice daily in random order for 28 d. A biochemical response was defined as a reduction in GH to no more than 2.5 microg/liter and normalization of IGF-I to age- and sex-matched controls. After 4 wk of octreotide, 9% of patients achieved a biochemical response. After 4 wk of pasireotide 200-600 microg s.c. bid, 19% of patients achieved a biochemical response, which increased to 27% after 3 months of pasireotide; 39% of patients had a more than 20% reduction in pituitary tumor volume. Pasireotide was generally well tolerated. Pasireotide is a promising treatment for acromegaly. Larger studies of longer duration evaluating the efficacy and safety of pasireotide in patients with acromegaly are ongoing.
    The Journal of clinical endocrinology and metabolism 06/2010; 95(6):2781-9. · 6.50 Impact Factor
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    ABSTRACT: There is currently no medical therapy for Cushing's disease that targets the pituitary adenoma. Availability of such a medical therapy would be a valuable therapeutic option for the management of this disorder. Our objective was to evaluate the short-term efficacy of the novel multireceptor ligand somatostatin analog pasireotide in patients with de novo, persistent, or recurrent Cushing's disease. We conducted a phase II, proof-of-concept, open-label, single-arm, 15-d multicenter study. Thirty-nine patients with either de novo Cushing's disease who were candidates for pituitary surgery or with persistent or recurrent Cushing's disease after surgery without having received prior pituitary irradiation. Intervention: Patients self-administered sc pasireotide 600 microg twice daily for 15 d. Normalization of urinary free cortisol (UFC) levels after 15 d treatment was the main outcome measure. Of the 29 patients in the primary efficacy analysis, 22 (76%) showed a reduction in UFC levels, of whom five (17%) had normal UFC levels (responders), after 15 d of treatment with pasireotide. Serum cortisol levels and plasma ACTH levels were also reduced. Steady-state plasma concentrations of pasireotide were achieved within 5 d of treatment. Responders appeared to have higher pasireotide exposure than nonresponders. Pasireotide produced a decrease in UFC levels in 76% of patients with Cushing's disease during the treatment period of 15 d, with direct effects on ACTH release. These results suggest that pasireotide holds promise as an effective medical treatment for this disorder.
    Journal of Clinical Endocrinology &amp Metabolism 11/2008; 94(1):115-22. · 6.43 Impact Factor