Plasma Octreotide Levels Research Articles

SAT-432 MTD201 Has a Favourable 28-Day Sustained Release Profile Compared to Sandostatin LAR in Healthy Subjects

A double-blind, randomised, single-dose parallel group study was performed to compare the tolerability, pharmacokinetics and pharmacodynamics of MTD201 30 mg octreotide (test product) and Sandostatin LAR 30 mg (reference product) in healthy subjects. MTD201 uses Q-Sphera™ printing technology to precisely control microparticle size, which facilitates simpler reconstitution and injection using smaller needle size than Sandostatin LAR (SLAR) or Somatuline Autogel. MTD201 is being developed for acromegaly and NETs as an alternative to these existing long-acting treatments. Methods: 24 male and female healthy subjects were randomised to receive a single, 30mg i.m. injection of MTD201 (N=12) using a 21G needle or Sandostatin LAR (N=12) using the pre-packed 19G needle. Plasma samples for determination of octreotide, growth hormone (GH) and IGF-1 concentrations were obtained throughout the 63-day period after injection. The plasma GH response to a GHRH+arginine challenge, an accepted surrogate efficacy endpoint for somatostatin analogues, was performed 7 days before octreotide dosing and repeated 28- and 45-days post-dose. Additional data were collected to check for presence of anti-octreotide antibodies and injection site reactions were scored regularly for 7 days post-injection. Results: Both treatments were well tolerated, with AEs consistent with octreotide treatment. Overall plasma octreotide exposures for the test and reference drugs were comparable whilst subjects receiving MTD201 illustrated lower initial spike in plasma octreotide (burst; 0.12ng/mL and 0.99ng/mL for MTD201 and SLAR, respectively), a more linear, consistent profile, and lower variability across the intended dose interval (28 days). Both treatment groups showed detectable plasma octreotide levels up to the final PK sampling point of 63 days. GH and IGF-1 suppression were highly comparable across treatments, with ≈25% and ≈30% reductions from baseline for both groups, respectively. Injection site reactions were less frequent and of lower severity in subjects who received MTD201. Specifically, pain at the injection site was observed in 8% (MTD201) and 25% (SLAR) of subjects, and injection site tenderness in 8% (MTD201) and 83% (SLAR) of subjects. Conclusions: MTD201 produced a safe and effective sustained-release profile of octreotide, supporting a once-monthly treatment interval, as is indicated for SLAR. Therapeutic octreotide concentrations and GH/IGF-1 suppression comparable with SLAR were achieved. Combined with the other advantages for MTD201 regarding smaller needle size, simpler and more reliable reconstitution and injection, these results warrant further study in a suitably powered clinical trial to formally establish MTD201 as an alternative long-acting somatostatin analogue product.

Successful treatment of congenital hyperinsulinism with long-acting release octreotide

Congenital hyperinsulinism (HI) is a common cause of hypoglycemia in infancy. The medical treatment of diazoxide-unresponsive HI is based on a somatostatin analogue. This study aims at replacing three daily s.c. octreotide (Sandostatin, Novartis) injections by a single and monthly i.m. injection of long-acting release (LAR) octreotide (Sandostatin LP, Novartis) in HI patients. LAR octreotide was injected every 4 weeks during 6 months and s.c. octreotide injections were stopped after the third injection of LAR octreotide. After this 6-month study, LAR octreotide was continued, with an average follow-up of 17 months. Ten HI pediatric patients unresponsive to diazoxide and currently treated with s.c. octreotide were included in the trial. Glycemias and other parameters (HbA1c, IGF1, height, weight, quality of life (QoL), and satisfaction) were monitored at each monthly visit. For all ten patients, glycemias were maintained in the usual range, HbAlc (mean 5.5%; 95% CI: 4.6-6.2) and IGF1 (mean 89.7 ng/ml; 95% CI: 26-153) were unchanged. Patients gained height significantly (mean 2.7 cm; 95% CI: 1.9-3.4) and no side effect was noted during the study and the later follow-up. Plasma octreotide levels were stable under LAR octreotide. Parents' questionnaires of general satisfaction were highly positive whereas children's QoL evaluation remained unchanged. In these diazoxide-unresponsive HI patients, LAR octreotide was efficient, well tolerated and contributed to a clear simplification of the medical care.

A Prospective Trial on the Effect of Body Mass Index and Sex on Plasma Octreotide Levels in Patients Undergoing Long-Term Octreotide LAR Therapy

Octreotide long acting repeatable (LAR) is commonly used to control the symptoms of patients with functional neuroendocrine tumors. Unfortunately, most patients escape control over time and require higher LAR doses or more frequent rescue therapy to remain asymptomatic. Previous work has shown that body weight and monthly LAR dose will significantly affect circulating plasma octreotide levels in patients undergoing therapy. To determine if other parameters change circulating plasma octreotide levels, we prospectively studied 82 patients undergoing long-term LAR therapy. Multivariate analysis demonstrated that the plasma octreotide levels decrease by approximately 3.4% for each unit of body mass index (BMI) increase (P = 0.03), adjusting for sex and monthly LAR dose. Plasma octreotide levels for females were approximately 47.6% higher than those for males (P = 0.045), adjusting for BMI and monthly LAR dose. Initial and subsequent octreotide LAR doses should take into consideration sex and BMI. Males are estimated to require 14.1-mg (SD, 7.25) higher monthly LAR doses than females with the same BMI. We have shown that plasma octreotide levels are affected by not only monthly LAR dose but also BMI and sex. We hope these observations will make choosing initial and subsequent octreotide LAR doses easier for physicians.

Clinical Value of Monitoring Plasma Octreotide Levels During Chronic Octreotide Long-Acting Repeatable Therapy in Carcinoid Patients

Octreotide is used to treat patients with neuroendocrine tumors. Previous reports show that octreotide long-acting repeatable (LAR) dose and patient body weight affect nadir plasma octreotide levels (approximately 1250, 2500, 5000, and 11,000 pg/mL for LAR doses of 10, 20, 30 and 60 mg/mo). However, plasma octreotide levels have decreased over time in patients receiving these doses of LAR. From November 2004 until July 2007, trough plasma octreotide levels were determined in 86 patients on long-term octreotide LAR therapy at doses of 30, 60, and 120 mg/mo. Changes in plasma drug levels were analyzed over time using random effects models. Current plasma octreotide levels for octreotide LAR doses of 30, 60, and 120 mg/mo are approximately 2200, 5200, and 6500 pg/mL, respectively, representing a decrease of approximately 50% to 70% compared with previously reported plasma octreotide levels. The decreases in octreotide levels over time with the 30- and 60-mg/mo LAR doses are highly statistically significant (P = 0.0067, 0.0149, respectively). Current plasma octreotide values are significantly lower than previously reported for 30-, 60-, and 120-mg/mo LAR doses. Serial plasma octreotide value measurements should be used to determine if increasing symptoms or tumor growth are associated with suboptimal octreotide levels.

Validation of Serum Versus Plasma Measurements of Chromogranin A Levels in Patients With Carcinoid Tumors

Chromogranin A (CGA) levels are used to confirm the diagnosis and monitor the course of patients with neuroendocrine tumors. Chromogranin A levels are significantly reduced when patients are acutely treated with octreotide; however, limited data are available that correlates octreotide long-acting repeatable (LAR) dose or steady state octreotide blood levels to the absolute value of serum or plasma CGA. Plasma, serum, and clinical information on carcinoid syndrome symptoms were collected anonymously from 40 patients treated with long-term octreotide LAR therapy for carcinoid syndrome. We found a strong positive linear relationship exists between serum and plasma CGA levels (r = 0.9858, P < 0.0001). No correlation existed between plasma octreotide levels or LAR dose and the static, absolute plasma/serum CGA levels. Although, higher mean CGA values were seen in the group whose diarrhea was "not under optimal control" than for the group "under optimal control," these results did not reach statistical significance (P = 0.24). Contrary to our hypotheses, a statistically significant inverse relationship was found between the frequency of flushing and the CGA levels (P = 0.0372). Higher mean CGA values were observed in the "under optimal control" group with flushing symptoms. Either serum or plasma can be used to measure CGA levels. Absolute (static) CGA levels do not positively correlate with symptom intensity during LAR therapy. Dynamic (serial) measurements of CGA are necessary to monitor the effectiveness of medical or surgical therapy.

Effect of Octreotide LAR Dose and Weight on Octreotide Blood Levels in Patients With Neuroendocrine Tumors

Octreotide long acting repeatable (LAR) is widely used for the control of symptoms of functional neuroendocrine tumors. At doses of 30 mg/mo, up to 40% of patients require subcutaneous octreotide "rescue" and up to 40% of patients are given more than 30 mg of LAR/mo. Octreotide acetate binds to the sst2 receptor with an affinity (Kd) of approximately 1 x 10(-9) mol/L (approximately equal to 1000 pg/mL), but higher (approximately equal to 10,000 pg/mL) concentrations of octreotide are required to completely saturate this receptor. Octreotide blood level measurement may be useful to guide LAR therapy in symptomatic patients or in patients who have tumor growth on traditional LAR doses. We hypothesize that LAR doses of 60 mg/mo will produce blood levels of 10,000 pg/mL or greater. At identical monthly LAR doses, patients with higher weights will require more medication to achieve similar plasma octreotide levels than individuals with lower body weights. Trough plasma, serum, urine, and saliva octreotide levels were obtained from 52 patients with carcinoid syndrome receiving 20 (n = 8), 30 (n = 19), or 60 mg LAR/mo (n = 10). Octreotide levels were determined by radioimmunoassay. The mean +/- SD plasma octreotide levels for patients receiving 20, 30, or 60 mg LAR/mo were 2518 +/- 1020, 5241 +/- 3004, and 10,925 +/- 5330 pg/mL, respectively. Patient weight (kilograms) was inversely related to plasma octreotide levels. There was a significant correlation between plasma octreotide levels and octreotide levels measured in urine, saliva, and serum. Frequent measurement of octreotide levels may be useful to guide octreotide therapy in patients with poorly controlled symptoms or those patients experiencing tumor growth.

Octreotide acetate (LAR) dose effect on plasma octreotide levels: Impact on neuroendocrine tumor management

3177 Background: Octreotide acetate (LAR) is commonly used for symptom control in carcinoid tumors. At doses of 20 or 30 mg, up to 40% of carcinoid patients require additional aqueous octreotide several times a week for symptom control. 20–40% of patients receiving LAR are given monthly doses higher than the current maximum recommended 30 mg dose. This implies that patients may need higher octreotide blood levels than 20 or 30mg LAR doses can provide. In vitro, octreotide acetate binds to the sst 2 receptor with an affinity (Kd, 50% receptor saturation) of 1x10-9 M (≈1,000 pg /ml) but higher (≈10,000 pg/ml) concentrations of octreotide are required for saturation. Aim: The current study determined the plasma octreotide levels in patients receiving 20, 30 or 60 mg/month of LAR and calculated the effect of weight BSA and BMI on drug levels. Methods: Thirty- seven patients from the www.Yahoo.com carcinoid group sent height and weight information and sent plasma and serum samples for octreotide levels, determined by specific and sensitive RIA. Samples were drawn immediately before the patient’s next dose of LAR. Patients were on 20mg (n=8), 30mg (n=19) or 60 mg/month (n=10) of LAR. Results: Serum and plasma octreotide levels in individuals were essentially identical (p= ns, ANOVA). Mean ± SD plasma octreotide levels for patients receiving 20, 30 or 60 mg/month LAR doses were 2,518 ±1,020, 5,241± 3,004 and 10,926 ± 5,530 pg/ml respectively. No adverse events were reported with patients receiving 60 mg/month LAR dose. Weight, BSA and BMI were inversely related to plasma octreotide levels. Conclusions: The clinical availability of a plasma octreotide assay may be useful to guide octreotide therapy in patients with poorly controlled symptoms or those with progressive tumor growth. Circulating octreotide levels in patients receiving 20 or 30 mg/month LAR doses are often inadequate to saturate sst 2. These individuals may require LAR doses of 60 mg/month to completely saturate sst 2 and optimize symptom or tumor control. The decision to increase LAR doses should be made with the help of plasma octreotide level measurements. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis

Somatostatin receptor gene transfer inhibits established pancreatic cancer xenografts

Background.Most human pancreatic adenocarcinoma cells do not express somatostatin receptors, and somatostatin does not inhibit the growth of these cancers. We have demonstrated previously that somatostatin inhibits the growth of pancreatic cancers expressing somatostatin receptor subtype-2 (SSTR2), but not receptor-negative cancers. SSTR2 expression may be an important tumor-suppressor pathway that is lost in human pancreatic cancer. We hypothesized that SSTR2 gene transfer would restore the growth-inhibitory response of human pancreatic cancer to somatostatin. Materials and methods.Palpable human pancreatic adenocarcinoma tumors were established on the backs of nude mice by subcutaneous injection of cultured cells (Panc-1). The animals were divided into 5 groups ( n = 10/group). Group I served as an untreated control. Group II received an intramuscular injection of the long-acting somatostatin analogue Sandostatin LAR. Group III received Lac-Z expressing adenovirus via intraperitoneal injection. Group IV received SSTR2 expressing adenovirus via intraperitoneal injection. Group V received SSTR2 expressing adenovirus via intraperitoneal injection and an intramuscular injection of Sandostatin LAR. The rate of tumor growth was assessed with calipers. After 28 days, the animals were anesthetized and exsanguanated, and the tumors were excised and weighed. Plasma somatostatin and octreotide levels were measured by radioimmunoassay. Expression of cell-surface somatostatin-receptor protein and known tumor-suppressor proteins was determined by reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry. Results.Systemic delivery of SSTR2-expressing adenovirus by intraperitoneal injection resulted in expression of SSTR2 protein in the subcutaneous human pancreatic cancers. Final tumor weight was significantly decreased in the groups expressing SSTR2 receptors compared to the other 3 groups. Treatment with Sandostatin LAR increased plasma octreotide levels as determined by radioimmunoassay, but had no significant effect on tumor growth. Western blot analysis revealed an up-regulation of the cyclin-dependent kinase inhibitors p27 and p16 in the SSTR2 transfected tumors. Conclusions.Expression of SSTR2 by human pancreatic cancer causes significant slowing of tumor growth by a mechanism independent of exogenous somatostatin. The mechanism may involve up-regulation of known tumor-suppressor proteins. Restoration of SSTR2 gene expression deserves further study as a potential gene-therapy strategy in human pancreatic cancer.

Generation of growth hormone pulsatility in women: evidence against somatostatin withdrawal as pulse initiator.

To test whether endogenous hypothalamic somatostatin (SRIH) fluctuations are playing a role in the generation of growth hormone (GH) pulses, continuous subcutaneous octreotide infusion (16 microg/h) was used to create constant supraphysiological somatostatinergic tone. Six healthy postmenopausal women (age 67 +/- 3 yr, body mass index 24.7 +/- 1.2 kg/m(2)) were studied during normal saline and octreotide infusion providing stable plasma octreotide levels of 2,567 +/- 37 pg/ml. Blood samples were obtained every 10 min for 24 h, and plasma GH was measured with a sensitive chemiluminometric assay. Octreotide infusion suppressed 24-h mean GH by 84 +/- 3% (P = 0.00026), GH pulse amplitude by 90 +/- 3% (P = 0.00031), and trough GH by 54 +/- 5% (P = 0.0012), whereas GH pulse frequency remained unchanged. The response of GH to GH-releasing hormone (GHRH) was not suppressed, and the GH response to GH-releasing peptide-6 (GHRP-6) was unaffected. We conclude that, in women, periodic declines in hypothalamic SRIH secretion are not the driving force of endogenous GH pulses, which are most likely due to episodic release of GHRH and/or the endogenous GHRP-like ligand.

Effects of octreotide, a somatostatin analogue, on initiation of pancreatic carcinogenesis in hamsters with N-nitrosobis(2-oxopropyl)amine

The modifying effects of octreotide acetate, a somatostatin (SMS) analogue shown to inhibit secretion of digestive enzymes, bicarbonate and pancreatic juice, on the initiation phase of pancreatic carcinogenesis were investigated in hamsters simultaneously treated with N-nitrosobis(2-oxopropyl)amine (BOP). Groups 1–3, each consisting of 20 animals, were given BOP subcutaneously once a week three times at a dose of 10 mg/kg body weight during administration of octreotide acetate for 28 days via osmotic pumps implanted subcutaneously at doses of 6 μg/day (group 1), 3 μg/day (group 2) or 0 μg/day (saline) (group 3). Group 4–6 animals (each group ten animals) were similarly administered octreotide acetate for the same period with five subcutaneous injections of saline. At the termination of experimental week 40, the incidences and multiplicities of pancreatic ductal adenocarcinomas and dysplastic lesions did not significantly differ among groups 1–3. No neoplastic lesions were found in groups 4–6. Subcutaneous administration of octreotide acetate resulted in obviously increased plasma octreotide levels. Our results thus suggest that this SMS analogue may not modulate the initiation of BOP-induced pancreatic carcinogenesis, regardless of its pharmacological action.

THE INFLUENCE OF OCTREOTIDE TREATMENT ON PULSATILE GROWTH HORMONE RELEASE IN ACROMEGALY

The pulsatile release of GH was investigated in eight active acromegalic patients before and during a subcutaneous infusion of 300 micrograms octreotide/24 h for 4 weeks. The number of GH pulses increased from a basal value of 14.4/24h to 16.3/24h during octreotide therapy. At the same time the mean GH concentration, valley concentration, peak height and amplitude decreased significantly. The inhibitory effect of octreotide on pulse characteristics did not depend on the time of day. IGF-I levels also decreased significantly; in five patients normal levels were reached. IGF-I levels correlated significantly with the mean GH level (r = 0.714, P less than 0.001), mean valley concentration (r = 0.697, P less than 0.001) and, to a lesser extent, area under the curve (r = 0.436, P = 0.033), but not the number of pulses. Plasma octreotide levels did not correlate with pulse parameters. In all but one patient a circadian rhythm was present during both the basal study and octreotide therapy. Compared with surgically treated acromegalics, the number of GH pulses was higher in untreated and octreotide-treated patients. This study demonstrates the pulsatile release of GH in active acromegaly both before and during octreotide therapy. This result suggests that endogenous GHRH is important for the generation of GH pulses in this disease.

Continuous subcutaneous octreotide infusion markedly suppresses IGF-I levels whilst only partially suppressing GH secretion in diabetics with retinopathy

The response to GH releasing hormone (GHRH 1-29) and 24-h serum GH and IGF-I levels were measured in 9 insulin-dependent diabetics with retinopathy and 6 normal volunteers before and after different treatment regimens with octreotide, a long-acting somatostatin analogue. Octreotide, 50 micrograms by sc injection, completely suppressed GHRH-stimulated GH release in both groups. Thrice daily sc injections for up to 20 weeks were associated with variable plasma octreotide levels and failed completely to suppress GH secretion in either the patients or the normal controls. Three days of continuous sc pump infusion (500 micrograms/24-h) resulted in consistently high plasma octreotide levels and completely suppressed 24-h GH in 4 normal subjects, whilst treatment for up to 16 weeks only partially suppressed GH levels in 6 patients (AUC mU.l-1.h-1; 209 +/- 81 vs 121 +/- 82; P = 0.01). Mean +/- SD IGF-I levels (micrograms/l) in the patients (but not controls) were suppressed into the hypopituitary range by median 6 weeks (range 2-16) pump administration (203 +/- 62 vs 60 +/- 25; P = 0.02). Pump treatment achieved total GH suppression in normal subjects; diabetics with retinopathy seem more resistant to the GH suppressing effects of the drug. However, the reduction of serum IGF-I with prolonged treatment may be of clinical value in arresting the progress of diabetic retinopathy.