Pasireotide (SOM230) shows efficacy and tolerability in the treatment of patients with advanced neuroendocrine tumors refractory or resistant to octreotide LAR: results from a phase II study

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.     

Phase I study of pasireotide (SOM 230) and everolimus (RAD001) in advanced neuroendocrine tumors

Octreotide and everolimus have demonstrated efficacy in neuroendocrine tumors. Pasireotide is a somatostatin analog with binding affinity to a broader range of somatostatin receptor subtypes than octreotide. We performed a phase I study to evaluate the safety and feasibility of combining pasireotide with everolimus in patients with advanced neuroendocrine tumors. Cohorts of patients with advanced neuroendocrine tumors were treated with escalating doses of pasireotide (600-1200?μg s.c. b.i.d., followed by pasireotide LAR 40-60?mg i.m. monthly) and everolimus (5-10?mg daily). Twenty-one patients were treated. Dose-limiting toxicities consisting of grade 3 rash and grade 3 diarrhea were observed. Twelve patients were safely treated at the maximum protocol-defined dose level of pasireotide LAR 60?mg i.m. monthly and everolimus 10?mg daily. Hyperglycemia was common; other observed toxicities were consistent with the known toxicities of either agent alone. Partial tumor response was observed in one patient; 17 (81%) patients experienced at least some tumor regression as their best response to therapy. In conclusion, pasireotide LAR 60?mg i.m. monthly in combination with everolimus 10?mg daily is feasible and associated with preliminary evidence of antitumor activity in patients with advanced neuroendocrine tumors. Further studies evaluating this combination are warranted.     

Management of hyperglycemia associated with pasireotide (SOM230): Healthy volunteer study

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.     

The duration of bronchodilation of salmeterol and salbutamol as measured by specific airway conductance in healthy subjects

According to the duration of bronchodilation, beta-2-agonists are divided into short and long acting bronchodilators. The bronchodilatory effect of available long acting beta-2-agonists (LABAs) beyond 12?h is not sufficiently studied. In order to evaluate the bronchodilatory effects of LABA in subjects without airway obstruction, the measurement of specific airway conductance (sGaw) with whole body plethysmography has been demonstrated to be a sensitive method. We aimed to determine the bronchodilatory effects of single doses of salmeterol 25, 50 and 200?μg and salbutamol 200?μg in healthy subjects (n?=?16) over a 24?h period in a randomized, double-blind, triple-dummy, placebo-controlled cross-over-study. At the 12-h endpoint, all three doses of salmeterol significantly increased sGaw compared with placebo. At the 24-h endpoint, there was a significant increase in sGaw with salmeterol 200?μg, while with 25 and 50?μg salmeterol the sGaw increase failed to reach statistical significance. There was no statistically significant increase in sGaw with salbutamol 200?μg at either the 12-h or 24-h endpoints. For weighted means, all three salmeterol doses showed statistically significant increase in sGaw compared with placebo over 0-12, 12-24 and 0-24?h periods, while for salbutamol 200?μg a significant increase in sGaw was recorded only over 0-12?h period. We conclude that sGaw measurement is a suitable method for recording the bronchodilatory effect of beta-2-agonists in healthy subjects. Using this method we could demonstrate that salmeterol 200?μg provides significant increase in specific airway conductance up to 24?h after a single dose.     

Long-term efficacy and safety of subcutaneous pasireotide in acromegaly: results from an open-ended,multicenter, Phase II extension study

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.     

A prospective longitudinal study of Pasireotide in Nelson’s syndrome

Purpose

Nelson’s syndrome is a challenging condition that can develop following bilateral adrenalectomy for Cushing’s disease, with high circulating ACTH levels, pigmentation and an invasive pituitary tumor. There is no established medical therapy. The aim of the study was to assess the effects of pasireotide on plasma ACTH and tumor volume in Nelson’s syndrome.

Methods

Open labeled multicenter longitudinal trial in three steps: (1) a placebo-controlled acute response test; (2) 1 month pasireotide 300–600 μg s.c. twice-daily; (3) 6 months pasireotide long-acting-release (LAR) 40–60 mg monthly.

Results

Seven patients had s.c. treatment and 5 proceeded to LAR treatment. There was a significant reduction in morning plasma ACTH during treatment (mean?±?SD; 1823?±?1286 ng/l vs. 888.0?±?812.8 ng/l during the s.c. phase vs. 829.0?±?1171 ng/l during the LAR phase, p?<?0.0001). Analysis of ACTH levels using a random intercept linear mixed-random effects longitudinal model showed that ACTH (before the morning dose of glucocorticoids) declined significantly by 26.1 ng/l per week during the 28-week of treatment (95% CI ??45.2 to ??7.1, p?<?0.01). An acute response to a test dose predicted outcome in 4/5 patients. Overall, there was no significant change in tumor volumes (1.4?±?0.9 vs. 1.3?±?1.0, p?=?0.86). Four patients withdrew during the study. Hyperglycemia occurred in 6 patients.

Conclusions

Pasireotide lowers plasma ACTH levels in patients with Nelson’s syndrome. A longer period of treatment may be needed to assess the effects of pasireotide on tumor volume.Trial registration: Clinical Trials.gov ID, NCT01617733

     

Safety and pharmacokinetics of multiple doses of aclidinium bromide administered twice daily in healthy volunteers

Chronic obstructive pulmonary disease (COPD) is characterized by progressive airway obstruction and increased cholinergic tone. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend long-acting anticholinergics for COPD maintenance treatment. Aclidinium bromide is a novel, long-acting muscarinic antagonist developed for the treatment of COPD. A Phase I, randomized, single-blind, multiple-dose clinical trial was conducted to assess the safety and pharmacokinetics (PK) of multiple doses of twice-daily (BID) aclidinium in healthy subjects. Thirty healthy male and female subjects received aclidinium 200 μg, 400 μg, 800 μg, or placebo twice daily for 7 days. Subjects were randomized to 1 of 3 cohorts and 10 subjects in each cohort were randomized (8:2) to either aclidinium or placebo groups. Safety was assessed via adverse events (AEs), laboratory evaluations, vital signs, and ECGs. Plasma samples were obtained at multiple time points throughout the study and analyzed for aclidinium and its inactive acid and alcohol metabolites using a fully validated method of liquid chromatography coupled with tandem mass spectrometry. A total of 9 treatment-emergent AEs were reported (1, placebo; 3, aclidinium 400 μg; 5, aclidinium 800 μg), all of which were mild in severity. No serious AEs were reported. There were no clinically meaningful changes in laboratory parameters or vital signs. PK parameters on Day 7 following BID dosing of aclidinium showed that steady state was achieved for aclidinium and its metabolites. On Days 1 and 7, maximum plasma concentrations (C_max) of aclidinium were generally observed at the first PK time point (5 min postdose) and rapidly declined, with plasma concentrations generally less than 10% of C_max by 6 h postdose in all aclidinium groups. Mean effective t_½ after the evening dose on Day 7 ranged from 4.6 to 7.0 h for aclidinium 400 μg and 800 μg, similar to the terminal t_½ observed on Day 1 (4.5–5.9 h). Exposure for aclidinium and both metabolites increased with increasing dose, with the increase in exposure being less than dose proportional between the 400 μg and 800 μg doses. Overall, all doses of aclidinium were safe and well tolerated throughout the study. Pharmacokinetic steady state was reached for aclidinium and both metabolites within the 7-day treatment period for all doses tested. Aclidinium bromide exhibited time-independent PK following dosing to steady state, indicating that similar concentration versus time profiles will occur after repeated administration at the same dose and frequency.     

替比夫定的药代动力学研究

目的评价中国健康志愿者单次口服不同剂量替比夫定的药代动力学特征以及多次给药后的稳态血浆药代动力学。方法42名年龄在18～40岁的健康志愿者,男32名,女10名,随机分配到200、400、600、800mg 4个剂量组。其中600mg剂量组受试者接受单剂量和多剂量的研究。多剂量每日给药,持续8d。采用HPLC-MS/MS法测定给药前和给药后不同时间替比夫定的主血浆、尿液药物浓度,并据此计算药代动力学参数。结果在单次口服200、400、600、800mg片剂后,受试者的达峰时间分别为2．50、2．00、2．00h和2．50h；半衰期的平均值分别为(43．3±15．2)h、(49．1±14．4)h、(39．4±12．1)h和(46．7±20．8)h；血药达峰浓度平均值分别为(1 753．2±389．0)ng/ml、(2 586．7±871．4)ng/ml、(3 703．6±1 219．0)ng/ml和(3 454．6±953．9)ng/ml；曲线下面积的平均值分别为(12 843．2±2 925．6)ng·h ~(1·)ml~1、(22 948．9±5 721．0)ng·~(1·)ml~1、(26 440．5±8 938．1)ng·h ~(1·)ml~1以及(28 820．9±7 912．9)ng·h ~(1·)ml~1；血浆清除率(600mg)为(6 545．6±1 504．4)ml/h；多次给药后的稳态药代动力学研究结果显示,在600mg/d的给药剂量下,连续给药8d后,平均稳态药时曲线下面积为(26 123．9±7 196．3)ng·h ~(1·)ml~1,平均血药浓度为(1 088．5±299．8)ng/ml,血药达峰浓度和曲线下面积蓄积囚子分别为1．02±0．21和1．23±0．26。结论受试者口服替比夫定以后,吸收较为迅速,给药后的2～3h即达到峰值。在200mg至800mg剂量范围内,血浆中替比夫定的药代动力学参数均呈现出一定的规律。替比夫定在受试者体内有轻微蓄积。     

Vilanterol trifenatate,a novel inhaled long-acting beta2 adrenoceptor agonist,is well tolerated in healthy subjects and demonstrates prolonged bronchodilation in subjects with asthma and COPD

Vilanterol (VI; GW642444M) is a novel inhaled long-acting β2-agonist with inherent 24 h activity in vitro in development as a combination with the inhaled corticosteroid fluticasone furoate for both COPD and asthma. These studies were conducted to determine the safety, tolerability, pharmacodynamics and pharmacokinetics of VI in healthy subjects and subjects with mild to moderate persistent asthma and moderate to severe COPD.Single doses of VI (25–100 μg) were given once daily to subjects with asthma and COPD and repeat doses once daily for 14 days to healthy subjects. Adverse events (AEs), vital signs, ECGs, pharmacodynamic endpoints, FEV₁ and VI plasma pharmacokinetics (AUC, Cmax and Tmax) were determined following dosing.VI (25–100 μg) was well tolerated. The incidence and severity of AEs were comparable to placebo. Following VI administration there were no clinically significant abnormalities in vital signs, 12-lead ECG, Holter ECG, blood glucose or potassium. There were no statistically significant effects on QTc of single and repeat VI doses up to 50 μg; some differences were seen following the 100 μg VI dose after single and repeat dose in healthy subjects and single dose in asthmatic subjects. All VI doses produced increases in FEV₁ from as early as 5 min after dosing which were maintained up to 24 h post-dose in subjects with asthma and COPD. In all subjects VI was rapidly absorbed (healthy subjects median Tmax at 5 min; asthma and COPD subjects median Tmax at 10 min) with systemic exposure increasing in an approximately dose proportional manner across the VI dose range. Marginal accumulation was seen on repeat dosing.Single doses of inhaled VI in subjects with asthma and COPD and repeat doses in healthy subjects were well tolerated with no clinically significant unwanted systemic effects. VI produced a rapid and prolonged bronchodilation over 24 h suggesting the potential for once daily administration.     

An investigation of the pharmacokinetics, pharmacodynamics, safety, and tolerability of ciclesonide hydrofluoroalkane nasal aerosol in healthy subjects and subjects with perennial allergic rhinitis

Ciclesonide hydrofluoroalkane nasal aerosol (CIC-HFA) is currently in development for treatment of allergic rhinitis. This Phase I study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of CIC-HFA in healthy subjects (N = 18) and subjects with perennial allergic rhinitis (PAR, N = 18) in a double-blind, placebo-controlled, 3-period crossover design following treatment with 282 μg or 148 μg CIC-HFA or placebo once-daily for 14 days. The concentrations of desisobutyryl-ciclesonide (des-CIC), the pharmacologically active metabolite of CIC were measured by a validated high performance liquid chromatography with tandem mass spectrometry. Maximum serum concentration (C(max)), area under the serum concentration time curve (AUC), time to maximum serum concentration (t(max)) and elimination half life (t(1/2)) where feasible, were calculated. Serum cortisol (AUC(0-24h)) and adverse events (AE) were also evaluated. The overall systemic exposure of des-CIC was low. The mean C(max) for des-CIC on Day 14 was 35.84 ng/L and 25.98 ng/L for the CIC-HFA 282 μg and CIC-HFA 148 μg treatment groups respectively. Mean AUC((0, last)) for des-CIC on Day 14 was 213 ng·h/L and 112.3 ng·h/L for CIC-HFA 282 μg and 148 μg respectively. Mean serum cortisol (AUC(0-24h)) was similar for CIC-HFA 282 μg (178 μg·h/dL), CIC-HFA 148 μg (169 μg·h/dL), and placebo (174 μg·h/dL) on Day 14. The overall incidence of AEs was low and headache and epistaxis were the most common individual AEs reported. In this study, systemic exposure of des-CIC was low and similar in healthy subjects and subjects with PAR with no evidence of clinically relevant accumulation over the 14 day treatment period in either treatment group. Both doses of CIC-HFA were well tolerated without significant effect on cortisol levels.     

Pasireotide (SOM230): development, mechanism of action and potential applications

Pasireotide (SOM230) is a multi-receptor ligand somatostatin analogue with high binding affinity for somatostatin receptor subtypes sst(1,2,3) and sst(5). Pasireotide potently suppresses GH, IGF-I and ACTH secretion, indicating potential efficacy in acromegaly and Cushing's disease. The prolonged inhibition of hormone secretion by pasireotide in animal models and expression of multiple sst receptors in carcinoid tumors suggests that pasireotide may have clinical advantages over octreotide in patients with carcinoid tumors. Direct and indirect antitumor activity has been observed in vitro with pasireotide, including sst receptor-mediated apoptosis and antiangiogenesis, suggesting a possible role for pasireotide in antineoplastic therapy. In summary, preclinical evidence, as well as preliminary results from clinical studies suggests that pasireotide is a promising new treatment for patients with symptoms of metastatic carcinoid tumors refractory or resistant to octreotide, de novo or persistent acromegaly, and that pasireotide has the potential to be the first directed medical therapy for Cushing's disease.     

Pharmacokinetics-based optimal dose prediction of donor source-dependent response to mycophenolate mofetil in unrelated hematopoietic cell transplantation

Mycophenolate mofetil (MMF) has been widely used for prophylaxis against graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-SCT). However, no clear advantage over methotrexate has been reported, other than reduced incidence of mucositis. We speculated that the wide inter-individual variation of plasma mycophenolic acid (MPA) levels veiled the benefits of MMF. Data from 36 unrelated allogeneic bone marrow (allo-BMT) and cord blood transplantation (CBT) were analyzed retrospectively based on MPA area under the curve (AUC(0-24h)). In allo-BMT, high AUC(0-24h) (>30?μg?h/ml) resulted in no incidence of grade II-IV acute/extensive chronic GVHD and tended to show higher overall and disease-free survival, lower relapse rates, and non-relapse mortality. In CBT, AUC(0-24h) less than 30?μg?h/ml was sufficient for low incidence of acute/chronic GVHD and high survival. Strong correlation between AUC(0-24h) and C(2h), plasma MPA concentration at 2?h after administration was observed. Single point assessment of C(2h) was shown to provide a useful surrogate of AUC(0-24h) to predict GVHD incidence. The results of this study suggest that individualized MMF dosing in a donor source-dependent fashion may be important for maximizing the benefit of MMF in allo-SCT.     

Chronic administration of nevirapine during pregnancy: impact of pregnancy on pharmacokinetics

OBJECTIVES: To determine the impact of pregnancy on the pharmacokinetics (PK) of nevirapine (NVP) during chronic dosing in HIV-infected women and appropriate NVP dosing in this population. METHODS: Twenty-six pregnant women participating in two open-label Pediatric AIDS Clinical Trials Group studies (P1022 and P1026S) were evaluated. Each patient received 200 mg NVP every 12 h and had PK evaluations during the second or third trimester; these evaluations were repeated postpartum. Paired maternal and cord blood NVP concentrations were collected at delivery in nine patients. Ante- and postpartum comparisons were made using paired t-tests and using a 'bioequivalence' approach to determine confidence interval (CI). RESULTS: The average NVP Area Under the Curve (AUC) was 56 +/- 13 mcg(*)h/mL antepartum and 61 +/- 15 mcg(*)h/mL postpartum. The typical parameters +/- standard error were apparent clearance (CL/F)=3.51 +/- 0.18 L/h and apparent volume of distribution (Vd/F)=121 +/- 19.8 L. There were no significant differences between antepartum and postpartum AUC or pre-dose concentrations. The AUC ratio was 0.90 with a 90% CI of the mean equal to 0.80-1.02. The median (+/- standard deviation) cord blood to maternal NVP concentration ratio was 0.91 +/- 0.90. CONCLUSIONS: Pregnancy does not alter NVP PK and the standard dose (200 mg every 12 h) is appropriate during pregnancy.     

Extended treatment of Cushing’s disease with pasireotide: results from a 2-year,Phase II study

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.

     

Managing pasireotide-associated hyperglycemia: a randomized,open-label,Phase IV study

Purpose

Pasireotide is an effective treatment for acromegaly and Cushing’s disease, although treatment-emergent hyperglycemia can occur. The objective of this study was to assess incretin-based therapy versus insulin for managing pasireotide-associated hyperglycemia uncontrolled by metformin/other permitted oral antidiabetic drugs.

Methods

Multicenter, randomized, open-label, Phase IV study comprising a core phase (≤?16-week pre-randomization period followed by 16-week randomized treatment period) and optional extension (ClinicalTrials.gov ID: NCT02060383). Adults with acromegaly (n?=?190) or Cushing’s disease (n?=?59) received long-acting (starting 40 mg IM/28 days) or subcutaneous pasireotide (starting 600 µg bid), respectively. Patients with increased fasting plasma glucose (≥?126 mg/dL on three consecutive days) during the 16-week pre-randomization period despite metformin/other oral antidiabetic drugs were randomized 1:1 to open-label incretin-based therapy (sitagliptin followed by liraglutide) or insulin for another 16 weeks. The primary objective was to evaluate the difference in mean change in HbA_1c from randomization to end of core phase between incretin-based therapy and insulin treatment arms.

Results

Eighty-one (32.5%) patients were randomized to incretin-based therapy (n?=?38 received sitagliptin, n?=?28 subsequently switched to liraglutide; n?=?12 received insulin as rescue therapy) or insulin (n?=?43). Adjusted mean change in HbA_1c between treatment arms was – 0.28% (95% CI – 0.63, 0.08) in favor of incretin-based therapy. The most common AE other than hyperglycemia was diarrhea (incretin-based therapy, 28.9%; insulin, 30.2%). Forty-six (18.5%) patients were managed on metformin (n?=?43)/other OAD (n?=?3), 103 (41.4%) patients did not require any oral antidiabetic drugs and 19 patients (7.6%) were receiving insulin at baseline and were not randomized.

Conclusion

Many patients receiving pasireotide do not develop hyperglycemia requiring oral antidiabetic drugs. Metformin is an effective initial treatment, followed by incretin-based therapy if needed.

ClinicalTrials.gov ID: NCT02060383.

     

Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin.

AIMS: This double-blind, parallel-group study was conducted to assess the pharmacodynamics, pharmacokinetics, and safety of AZD6140, the first oral, reversible adenosine diphosphate (ADP) receptor antagonist. METHODS AND RESULTS: Patients (n = 200) with atherosclerosis were randomized to receive AZD6140 50, 100, or 200 mg twice daily (bid) or 400 mg daily (qd) or clopidogrel 75 mg qd for 28 days. All groups received aspirin 75-100 mg qd. AZD6140 (100 and 200 mg bid, 400 mg qd) rapidly and nearly completely inhibited ADP-induced platelet aggregation after initial dosing (day 1) and at day 28. On day 1, peak final-extent inhibition of platelet aggregation (IPA) was observed 2-4 h post-dose with AZD6140, whereas clopidogrel minimally inhibited platelet aggregation (mean percentage IPA < 20%, all time points). Four hour post-dose at steady state, the three higher doses of AZD6140 produced comparable final-extent mean percentage IPA (approximately 90-95%), which exceeded that with AZD6140 50 mg bid or clopidogrel (approximately 60%). AZD6140 was generally well tolerated. All bleeding events, except one in a patient receiving 400 mg qd, were minor and of mild-to-moderate severity. CONCLUSION: AZD6140 100 and 200 mg bid were well tolerated and were superior to AZD6140 50 mg bid and clopidogrel 75 mg qd with regard to antiplatelet efficacy.     

Pasireotide does not prevent postoperative pancreatic fistula: a prospective study

Background

Pancreatic fistula is a major cause of morbidity after pancreas surgery. In 2014, a single-center, randomized-controlled trial found pasireotide decreased pancreatic fistula rates. However, this finding has not been validated, nor has pasireotide been widely adopted.

Effects of somatostatin analogs on glucose homeostasis in rats

Pasireotide (SOM230) is a multireceptor-targeted somatostatin analog with high binding affinity for sstr(1,2,3) and sstr(5). The effects of pasireotide and octreotide on blood glucose, insulin, and glucagon levels in rats were evaluated alone and in combination. Single-dose s.c. pasireotide acutely elevated plasma glucose, whereas single-dose s.c. octreotide had no or a small hypoglycemic effect. Glucose elevation with s.c. pasireotide was transient with tachyphylaxis after repeated or continuous administration. Pasireotide and octreotide caused similar inhibitory effects on insulin secretion, whereas pasireotide had a weaker inhibitory effect on glucagon secretion than octreotide. Continuous infusion of pasireotide or injection of pasireotide long-acting release (LAR) resulted in only small and transient elevations of plasma glucose. Based on these results, and differences in the sstr binding affinity of pasireotide vs octreotide, it was hypothesized that the sstr(5) vs sstr(2) receptor activation ratio is the main driver of hyperglycemia after pasireotide. The results also suggest that stronger activation of sstr(2) may counteract the hyperglycemic effect. Indeed, co-administration of octreotide, which has a high affinity for sstr(2), with a hyperglycemic dose of pasireotide did not cause significant changes in plasma glucose levels. In conclusion, although pasireotide and octreotide inhibited insulin to a similar degree, only pasireotide administration was associated with hyperglycemia. The strong glucagon inhibitory effect exhibited by octreotide but not pasireotide may explain this observation. The lack of hyperglycemia during co-administration of pasireotide and octreotide may be explained by the greater activation of sstr(2) compared with pasireotide alone, causing the insulin-glucagon balance to shift within the normoglycemic range. Extrapolation of these data to humans must account for species differences in islet cell sstr expression.     

Pharmacokinetic profile of lanreotide Autogel in patients with acromegaly after four deep subcutaneous injections of 60, 90 or 120 mg every 28 days

OBJECTIVE: To investigate the pharmacokinetic profile of a prolonged release, aqueous Autogel formulation of the somatostatin analogue lanreotide (Lan-ATG). DESIGN: A phase II, randomized, double-blind study, during which patients received 60, 90 or 120 mg Lan-ATG for four fixed administrations at 28-day intervals. PATIENTS: A total of 18 patients with acromegaly were recruited; six patients were randomized to each treatment. MEASUREMENTS: Lanreotide minimum concentration (C(min)), maximum serum concentration (C(max)) and area under the concentration-time curve during a dosing interval (AUC(tau)) were assessed after a single dose and at steady state (ss). Serum GH and IGF-1 levels were assessed before each administration and at the end of the study. RESULTS: After a single administration, dose proportionality for C(min,1), C(max) and AUC(tau) was demonstrated statistically. After repeated administrations, Lan-ATG exhibited linear pharmacokinetics over the dose range and ss values of C(min), C(max) and AUC(tau) increased in a dose-dependent, linear manner. Mean C(max,ss) values were only two- to fourfold greater than C(min,ss) values, and there was good control over the entire release profile. Serum levels of GH and IGF-1 declined over the course of the study and acromegaly symptoms improved. The treatment was well tolerated. CONCLUSIONS: Lan-ATG showed linear pharmacokinetic profiles over the three dose levels after both single and repeated dosing, no initial burst effect and good control over the entire release profile. Despite the absence of dose adaptation, four injections of Lan-ATG were effective in lowering serum levels of GH and IGF-1.