Blood clearance and occupational exposure for 177Lu-DOTATATE compared to 177Lu-PSMA radionuclide therapy.

The main target of this work is to examine blood clearance and external exposure for 177Lu-DOTATATE compared with new emerging 177Lu-PSMA therapy. Blood clearance and radiation exposure of 31 patients treated with 5.5 ± 1.1 GBq 177Lu-DOTATATE were compared to those of 23 patients treated with 7.4 GBq 177Lu-PSMA. Dose rates were measured at several distances and time points up to 120 h after treatment. Blood samples were collected conjunctively after infusion. Caregiver's cumulative dose was measured by means of an OSL (optically stimulated luminescence) dosimeter for 4-5 days and medical staff's dose was also estimated using electronic personal dosimeters. Finger dose was determined via ring TLD (Thermoluminescence Dosimeter) for radiopharmacists and nurses. Dose rates due to 177Lu-DOTATATE at a distance of 1 m, 4 h and 6 h after infusion, were 3.0 ± 2.8 and 2 ± 1.9 µSv/(h GBq), respectively, while those due to 177Lu-PSMA were 3.1 ± 0.8 and 2.2 ± 0.9 µSv/(h GBq). Total effective dose of 17 caregivers was 100-200 µSv for 177Lu-DOTATATE therapy. Mean effective doses to nurses and radiopharmacists were 5 and 4 µSv per patient, respectively, while those for physicists and physicians were 2 µSv per patient. For 177Lu-DOTATATE, effective half-life in blood and early elimination phase were 0.31 ± 0.13 and 4.5 ± 1 h, while they were found as 0.4 ± 0.1 and 5 ± 1 h, respectively, for 177Lu-PSMA. The first micturition time following 177Lu-DOTATATE infusion was noted after 36 ± 14 min, while the second and third voiding times were after 74 ± 9 and 128 ± 41 min, respectively. It is concluded that blood clearance and radiation exposure for 177Lu-DOTATATE are very similar to those for 177Lu-PSMA, and both treatment modalities are reasonably reliable for outpatient treatment, since the mean dose rate [2.1 µSv/(h GBq)] decreased below the dose rate that allows release of the patient from the hospital (20 µSv/h) after 6 h at 1 m distance.

The amount of injected 177Lu-octreotate strongly influences biodistribution and dosimetry in C57BL/6N mice.

BACKGROUND: (177)Lu-octreotate therapy has proven to give favorable results after treatment of patients with neuroendocrine tumors. Much focus has been on the binding and uptake of (177)Lu-octreotate in tumor tissue, but biodistribution properties in normal tissues is still not fully understood, and the effect of receptor saturation may be important. The aim of this study was to investigate the influence of the amount of (177)Lu-octreotate on the biodistribution of (177)Lu-octreotate in normal tissues in mice. MATERIAL AND METHODS: C57BL/6N female mice were intravenously injected with 0.1-150 MBq (177)Lu-octreotate (0.039 µg peptide/MBq). The mice were killed 0.25 h to 14 days after injection by cardiac puncture under anesthesia. Activity concentration was determined in blood, bone marrow, kidneys, liver, lungs, pancreas, and spleen, and mean absorbed doses were calculated. RESULTS: The activity concentration varied with time and amount of injected activity. At 4-8 h after injection, a local maximum in activity concentration was found for liver, lungs, pancreas, and spleen. With the exception for the lower injected activities (0.1-1 MBq), the overall highest uptake was found in the kidneys (%IA/g). Large variations were found and the activity concentration in kidneys was 11-23%IA/g at 4 h, and 0.22-1.9%IA/g at 7 days after injection. Furthermore, a clear reduction in activity concentration with increased injected activity was observed for lungs, pancreas and spleen. CONCLUSION: The activity concentration in all tissues investigated was strongly influenced by the amount of (177)Lu-octreotate injected. Large differences in mean absorbed dose per unit injected activity were found between low (0.1-1 MBq, 0.0039-0.039 µg) and moderate amounts (5-45 MBq, 0.2-1.8 µg). Furthermore, the results clearly showed the need for better ways to estimate absorbed dose to bone marrow other than methods based on a single blood sample analysis. Since the absorbed dose to critical organs will limit the amount of (177)Lu-octreotate administered, these findings must be taken into consideration when optimizing this type of therapy.

Effect of growth hormone on dawn phenomenon in patients with type 2 diabetes.

We aimed to investigate the involvement of growth hormone in dawn phenomenon and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). On six occasions separated by intervals of at least 3 days, subjects received early evening (16:00 hours) or late night (23:00 hours) pretreatment with subcutaneous injection of normal saline, human growth hormone, or octreotide. Modified euglycemic insulin clamp test was done 16 hours later and variable glucose infusion (M values) was determined. Plasma glucose, serum insulin, insulin-like growth factor-1, non-esterified fatty acids, and metabolic clearance rate of insulin (MCRI) were measured. Early evening application of growth hormone decreased MCRI 16 hours later, suggesting reduction in insulin sensitivity. Exogenous growth hormone injection reduced insulin sensitivity in T2DM patients. Results provide direct evidence for the role of growth hormone in regulating the insulin sensitivity in insulin-resistant patients.

Rapid blood clearance and lack of long-term renal toxicity of 177Lu-DOTATATE enables shortening of renoprotective amino acid infusion.

PURPOSE: The aim of the study was to investigate the feasibility of shortening the recommended 4-h renoprotective amino acid infusion in patients receiving peptide receptor chemoradionuclide therapy (PRCRT) using radiosensitizing 5-fluorouracil. We evaluated the clearance of radiopeptide from the blood, long-term nephrotoxicity in patients undergoing PRCRT with the conventional 4-h amino acid infusion and renal uptake in patients receiving an abbreviated infusion. METHODS: The whole-blood clearance of (177)Lu-DOTA-octreotate (LuTate) was measured in 13 patients receiving PRCRT. A retrospective analysis of short-term and long-term changes in glomerular filtration rate (GFR) in 96 consecutive patients receiving a 4-h infusion was performed. Renal LuTate retention estimated using quantitative SPECT/CT in 22 cycles delivered with a 2.5-h amino acid infusion was compared with that in 72 cycles with the 4-h infusion. RESULTS: LuTate demonstrated biexponential blood clearance with an initial clearance half-time of 21 min. Approximately 88 % of blood activity was cleared within 2 h. With the 4-h protocol, there was no significant change in GFR (1.2 ml/min mean increase from baseline; 95 % CI -6.9 to 4.4 ml/min) and no grade 3 or 4 nephrotoxicity at the end of induction PRCRT. The long-term decline in GFR after a median follow up of 22 months was 2.2 ml/min per year. There was no significant difference in the renal LuTate retention measured in patients receiving a 2.5-h amino acid infusion compared to those who had a 4-h infusion. CONCLUSION: The greatest renal exposure to circulating radiopeptide occurs in the first 1 - 2 h after injection. This, combined with the safety of LuTate PRCRT, allows consideration of an abbreviated amino acid infusion, increasing patient convenience and reducing human resource allocation.

The temporary drop of serum octreotide concentration deteriorated ventricular tachycardia in an acromegalic patient.

Acromegaly is frequently accompanied by left ventricular hypertrophy (LVH) which causes ventricular dysfunction. Ventricular arrhythmia is one of the important complications in acromegalic patients. Hypertrophic cardiomyopathy (HCM) is characterized by LVH with a nondilated chamber. About 10 % of HCM evolve into dilated phase of HCM, which is associated with an increased incidence of ventricular tachycardia (VT). However there is no report about a combination of dilated phase of HCM and VT in acromegalic patients. Octreotide is a somatostatin analog that has been used for medical therapy for acromegaly. We herein report that the first case of the change of serum octreotide concentration affected the control of VT, which was induced by dilated phase of HCM. A 56-year-old Japanese man was referred to our hospital for treatment of acromegaly. The patient was diagnosed the dilated phase of HCM with sustained VT. The frequency and severity of VT were gradually ameliorated by subcutaneous octreotide injection. However VT was deteriorated when its injection was changed to octreotide long-acting release (LAR) injection. The temporary drop in serum octreotide concentration was known at the transition from subcutaneous injection to LAR injection. This clinical course gives us the important information that subcutaneous octreotide injection for two weeks should be necessary to keep serum octreotide concentration when switing to octreotide LAR administration in acromegalic patients with severe arrhythmia.

A case of malignant insulinoma: successful control of glycemic fluctuation by replacing octreotide injections with octreotide LAR injections.

A 73-year-old woman with malignant insulinoma was treated with 100 µg/day octreotide for unresected insulinoma and liver metastases. The daily administration of the drug induced hyperglycemia after dinner in addition to existing fasting hypoglycemia possibly because this drug suppressed both insulin and glucagon secretion and its blood concentration was unstable. After replacing a daily injection of octreotide with a monthly injection of octreotide long-acting repeatable (LAR), blood glucose levels stabilized within the normal range. The findings of the present study showed that octreotide LAR could be useful for the long-term treatment of unresectable insulinomas.

Sustained-release delivery of octreotide from biodegradable polymeric microspheres.

The study reports on the drug release behavior of a potent synthetic somatostatin analogue, octreotide acetate, from biocompatible and biodegradable microspheres composed of poly-lactic-co-glycolic acid (PLGA) following a single intramuscular depot injection. The serum octreotide levels of three Oakwood Laboratories formulations and one Sandostatin LAR(®) formulation were compared. Three formulations of octreotide acetate-loaded PLGA microspheres were prepared by a solvent extraction and evaporation procedure using PLGA polymers with different molecular weights. The in vivo drug release study was conducted in male Sprague-Dawley rats. Blood samples were taken at predetermined time points for up to 70 days. Drug serum concentrations were quantified using a radioimmunoassay procedure consisting of radiolabeled octreotide. The three octreotide PLGA microsphere formulations and Sandostatin LAR(®) all showed a two-phase drug release profile (i.e., bimodal). The peak serum drug concentration of octreotide was reached in 30 min for all formulations followed by a decline after 6 h. Following this initial burst and decline, a second-release phase occurred after 3 days. This second-release phase exhibited sustained-release behavior, as the drug serum levels were discernible between days 7 and 42. Using pharmacokinetic computer simulations, it was estimated that the steady-state octreotide serum drug levels would be predicted to fall in the range of 40-130 pg/10 µL and 20-100 pg/10 µL following repeat dosing of the Oakwood formulations and Sandostatin LAR(®) every 28 days and every 42 days at a dose of 3 mg/rat, respectively.

Do Gut Hormones Contribute to Weight Loss and Glycaemic Outcomes after Bariatric Surgery?

Bariatric surgery is an effective intervention for management of obesity through treating dysregulated appetite and achieving long-term weight loss maintenance. Moreover, significant changes in glucose homeostasis are observed after bariatric surgery including, in some cases, type 2 diabetes remission from the early postoperative period and postprandial hypoglycaemia. Levels of a number of gut hormones are dramatically increased from the early period after Roux-en-Y gastric bypass and sleeve gastrectomy-the two most commonly performed bariatric procedures-and they have been suggested as important mediators of the observed changes in eating behaviour and glucose homeostasis postoperatively. In this review, we summarise the current evidence from human studies on the alterations of gut hormones after bariatric surgery and their impact on clinical outcomes postoperatively. Studies which assess the role of gut hormones after bariatric surgery on food intake, hunger, satiety and glucose homeostasis through octreotide use (a non-specific inhibitor of gut hormone secretion) as well as with exendin 9-39 (a specific glucagon-like peptide-1 receptor antagonist) are reviewed. The potential use of gut hormones as biomarkers of successful outcomes of bariatric surgery is also evaluated.

Effects of octreotide exposure during pregnancy in acromegaly.

BACKGROUND: Only six women who were treated with somatostatin analogues (SSAs) throughout their pregnancies have been described so far. The influence of SSAs on the course of pregnancy and newborn outcomes remains largely unknown. Many aspects of SSAs pharmacokinetics in mother and foetus have not yet been defined. METHODS AND FINDINGS: We report a case study on the effects of octreotide on uterine artery blood flow, octreotide concentrations in biological fluids of mother and newborn, and somatostatin (SST) receptor expression and binding at the level of the maternal-foetal barrier tissues in an acromegalic woman treated with short-acting octreotide throughout her pregnancy. An acute decrease in uterine artery blood flow was observed after octreotide injections, without affecting the pregnancy course, delivery, or foetal development. Octreotide concentrations were high in maternal serum and colostrum and lower in umbilical cord serum, amniotic fluid, and newborn serum. All SST receptor subtypes can be expressed in placental tissue but their binding profile was weak both in the placenta and umbilical cord. The child was healthy and developed normally up to age 6 from an anthropometric, metabolic, and endocrine point of view. We reviewed all published reports on pregnancy SSA exposure and outcomes were compared to a time-matched group of acromegalic women not exposed to SSA. No significant effect on the mother or foetus was observed. CONCLUSIONS: Short-acting octreotide appears not to affect the function of the maternal-foetal barrier or foetal development, except for the occurrence of acute, reversible, and clinically irrelevant haemodynamic changes. These data support the feasibility and safety of treatment with short-acting octreotide in acromegalic women during pregnancy and excludes major matters of concern about the effects of this medication on pregnancy itself and its outcome.

Primary intestinal lymphangiectasia in children: is octreotide an effective and safe option in the treatment?

OBJECTIVE: Octreotide has been suggested as a medical treatment option in refractory cases of primary intestinal lymphangiectasia (IL). There are few data about the long-term effect and safety of octreotide for IL in the literature. In the present article we analyzed pediatric cases of primary IL with long-term octreotide treatment and discussed its safety profile. METHODS: Between 1999 and 2008, 13 children were diagnosed in our clinic as having IL. Six patients with primary IL were followed up, receiving octreotide therapy. The clinical data of the patients and duration of therapy, dose, and side effects of octreotide were evaluated. RESULTS: Octreotide, 15 to 20 µg per body weight 2 times daily subcutaneously, was given to all of the patients. Duration of the octreotide treatment changed between 3 and 37 months. Stool frequency decreased in all of the patients after starting octreotide treatment. Serum albumin could be maintained at normal levels in 3 patients. The requirement of albumin infusions decreased in all of the patients. Acute pancreatitis was observed as a side effect of octreotide in 1 patient. CONCLUSIONS: Octreotide may help to maintain serum albumin levels, improve clinical findings, and decrease the requirement of albumin infusions in refractory cases of primary IL.

Post-extraction disulfide bond cleavage for MS/MS quantification of collision-induced dissociation-resistant cystine-cyclized peptides and its application to the ultra-sensitive UPLC-MS/MS bioanalysis of octreotide in plasma.

Disulfide-cyclized peptides, including the somatostatin receptor agonist octreotide, are usually resistant against collision-induced dissociation (CID) complicating their bioanalysis by MS/MS. Post-extraction reductive cleavage of the disulfide bridge of such peptides utilizing tris(2-carboxyethyl)phosphine generates the corresponding linear dithiol-peptides. This procedure enables monitoring of larger, specific fragments in CID which usually avoid matrix interference present for single amino acid iminium ions abundant in CID of the intact peptides. To assist formulation development for oral administration of the cystine-cyclized therapeutic peptide octreotide, we applied this methodology to the development of an ultra-sensitive UPLC-MS/MS assay for plasma octreotide and validated it according to FDA's and EMA's pertinent guidelines. Octreotide was extracted from plasma by fast and simple protein precipitation with acetonitrile and subsequently reduced to linear dithiol-octreotide for the monitoring of specific fragments in selected reaction monitoring. The calibrated concentration range of 10 (9.8 pM) to 20,000 pg mL-1 was linear with correlation coefficients > 0.99. Interday accuracy ranged between 100.0 and 108.9% with corresponding precision of <8.1%. The assay was successfully applied to the quantification of octreotide plasma concentrations after intravenous administration in beagle dogs. The presented procedure of disrupting the cyclic structure of cystine-cyclized peptides by reductive cleavage of the intramolecular disulfide bond enables the generation of more specific and intense fragments in CID can serve as a general methodology for the sensitive bioanalysis of cystine-bearing cyclic peptides.

Gel-electromembrane extraction of peptides: Determination of five hypothalamic agents in human plasma samples.

Agarose gel as a green membrane has been proposed for use in electromembrane extraction of five hypothalamic-related peptides without an ionic carrier. Octreotide, goserelin, triptorelin, cetrorelix, and somatostatin were extracted from 5.0 mL of sample solution (adjusted to pH 5.0) into a microvolume acceptor solution (HCl, 100 mM) under the applied voltage of 30 V in 15 min. The pH of the agarose gel 3.0% (w/v) was adjusted to 4.0 to facilitate the movement of peptides through the membrane. Quantification was performed using an HPLC-UV system on a C18 column. Quantification and detection limits were found to be in the range of 15.0-20.0 ng mL-1 and 4.5-6.0 ng mL-1, respectively. Dynamic linear ranges were found to be in the range of 15.0-1000 ng mL-1 (R2 > 0.995) and recoveries were in the range of 62.3-77.6%. The optimized method was applied to spiked human plasma samples. The method showed relative recoveries in the range of 44.8-66.0%. Finally, the proposed method was compared with and shown to have higher recoveries than, the conventional electromembrane extraction method for the peptides under study.

In Vivo Instability of 177Lu-DOTATATE During Peptide Receptor Radionuclide Therapy.

Peptide receptor radiotherapy using 177Lu-labeled somatostatin ligand analogs is a well-established treatment for neuroendocrine tumors, with 177Lu-DOTATATE having acquired marketing authorization in Europe and the United States. The investigation of the pharmacokinetics of these radiopharmaceuticals in vivo in humans is crucial for personalized treatment management and understanding of treatment effects. Such an investigation requires input data on the in vivo stability of the radiopharmaceuticals in blood and plasma. The work presented here is devoted to the investigation of the in vivo stability of 177Lu-DOTATATE in humans affected by neuroendocrine tumors. Methods: Blood samples of 6 patients undergoing 177Lu-DOTATATE were taken at 0.5, 4, 24, and 96 h after injection. Analysis of metabolic stability was performed using high-performance liquid chromatography. Results: A fast metabolism of the radiopharmaceutical was observed, with the fraction of intact 177Lu-DOTATATE in plasma decreasing rapidly to 23% ± 5% (mean ± SD) at 24 h and 1.7% ±0. 9% at 96 h after injection. Conclusion: The in vivo stability of 177Lu-DOTATATE is much lower than previously assumed, with the major part of radioactivity in plasma consisting of 177Lu-labeled metabolites already at 24 h after injection.

Control of octreotide release from silk fibroin microspheres.

Poly(d,l-lactide-co-glycolide) (PLGA) microspheres have been used as an injectable depot for prolonged release of octreotide (Sandostatin LAR®), a peptide drug for the treatment of acromegaly and gastrointestinal tumors. However, acylation and incomplete release of the encapsulated octreotide, as well as acidic degradation product-induced inflammation are the major challenges hampering widespread clinical applications of this delivery system. The purpose of this study was to develop a novel octreotide-delivering system utilizing naturally derived biodegradable material, silk fibroin (SF). Octreotide acetate was encapsulated in the SF microspheres with a high loading (8-10 wt%) using polyethylene glycol (PEG)-assisted emulsification method. The octreotide-SF microspheres exhibited a silk I structure (low crystallinity) and burst release in in vitro release studies. Ethanol treatment after microsphere formation significantly increased ß-sheet and silk II structure (high crystallinity) of the microspheres, significantly reducing the burst release and resulting in zero-order sustained release of octreotide over 102 days, and the data could be fit to the diffusion-driven release model. After the ethanol-treated microspheres were intramuscularly injected into rats at low (2 mg/kg) and high (8 mg/kg) octreotide doses, the plasma concentration of octreotide in the high dose group remained high (>50 pg/mL) at day 28 when compared to that of the control (pure drug at low dose) and low dose microsphere group. Interestingly, the plasma concentration for the high dose group at day 56 dramatically increased to >280 pg/mL observed at day 28. The low dose microsphere group showed a similar increase, but at a much lower level. The rebound octreotide level likely reflected degradation of the SF matrix which released tightly bound/trapped octreotide. Therefore, SF microspheres can deliver octreotide over a long period of time with release kinetics and the mechanism different from PLGA microsphere system.

Evaluation of the Interaction of Amino Acid Infusion on 177Lu-Dotatate Pharmacokinetics in Patients with Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND AND OBJECTIVE: 177Lu-Dotatate is a radio-labeled analog of somatostatin used in the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. In order to prevent nephrotoxic effects of 177Lu-Dotatate a co-infusion of amino acids (AA) is administered, resulting in a decrease in tubular renal reabsorption of 177Lu-Dotatate. This study aimed to quantify the impact of AA co-infusion on the pharmacokinetics of 177Lu-Dotatate in cancer patients and to evaluate its relationship with toxicity during the first treatment cycle (C1). METHODS: 7.4 GBq of 177Lu-Dotatate was administered to 42 patients over a 30-min intravenous infusion. Infusion of AA started 2 h before and continued for 6 h after the infusion of 177Lu-Dotatate. Radioactivity-time data (n = 346) were analyzed using NONMEM® (version 7.2.0). RESULTS: 177Lu-Dotatate pharmacokinetics was best described by a three-compartment model with first-order elimination. AA co-infusion had a significant effect ('fixed effect') on 177Lu-Dotatate pharmacokinetics, with a mean value of 1.5-fold (95% confidence interval 1.03-1.97) increase in the elimination rate constant (k10) from 0.204 to 0.306 h-1, but this AA co-infusion effect was associated with a large inter-individual variability (IIV) of 104%. The individual k10 values increased during concomitant AA infusion by a factor ranging from 1.01 to 21.3 for 27 patients, whereas the opposite effect was observed in 15 patients (range 0.36-0.99) of whom seven had a k10 value lower than 0.85. This variability in AA effect contributed to the variability in 177Lu-Dotatate plasma exposure (area under the concentration-time curve from time zero to Day 15 for C1 [AUCDay15]) that correlated with lymphopenia observed at Day 15 (p = 0.004). CONCLUSIONS: A substantial effect of AA co-infusion on 177Lu-Dotatate pharmacokinetics was shown but was associated with high IIV, contributing to IIV in hematological toxicity.

Effect of everolimus on the pharmacokinetics of octreotide long-acting repeatable in patients with advanced neuroendocrine tumors: An analysis of the randomized phase III RADIANT-2 trial.

In the RADIANT-2 trial, addition of everolimus to octreotide long-acting repeatable (LAR) exhibited a clinically meaningful 5.1-month improvement in progression-free survival (PFS) in patients with advanced functional neuroendocrine tumors. In this study, we characterized the effects of everolimus co-administration on octreotide LAR pharmacokinetics and its relationship with efficacy and safety. At least one evaluable blood everolimus and plasma octreotide predose minimum concentration (Cmin ) was available for 182 patients and 294 patients, respectively. Concomitant everolimus administration increased octreotide Cmin with a geometric mean ratio (everolimus/placebo) of 1.47 (90% confidence interval [CI] = 1.32-1.64). Risk for progression was consistently reduced when everolimus Cmin was increased twofold, regardless of octreotide exposure (hazard ratio [HR] = 0.74; 95% CI = 0.46-1.18; HR = 0.54; 95% CI = 0.32-0.92 for 6 ng/mL and 4 ng/mL octreotide, respectively). Risk for pulmonary or metabolic events was associated with increased everolimus Cmin . Co-administration of everolimus plus octreotide LAR increased octreotide Cmin , which did not impact efficacy.

A comparison of biodistribution between 111In-DTPA octreotide and 111In-DOTATOC in rats bearing pancreatic tumors.

111In-DTPA octreotide (DTPAOC) has been used for detecting somatostatin receptor positive tumor for years. In-111 DOTA-Tyr3-octreotide (DOTATOC) is newly developed for diagnostic and therapeutic purposes. In this study, we compared the biodistribution and tumor uptake ratio after injection of In-111 DTPAOC and In-111 DOTATOC in rats. Twelve rats bearing pancreatic tumors were divided into two groups: six rats were sacrificed at 4 hr after injection of 3.7 MBq of In-111 DTPAOC and another 6 rats were sacrificed at the same time after injection of 3.7 MBq of In-111 DOTATOC. Samples of various organs were obtained and counted to calculate the tissue concentration. In addition, 12 rats bearing pancreatic tumors were scanned at 4, 24, and 48 hr after injection of 37 MBq of In-111 DTPAOC or In-111 DOTATOC. The tumor uptake ratios (T/N ratio) were calculated. The biodistribution data showed that the activity in the tumor as well as in the kidney was significantly higher in the In-111 DOTATOC group than in the In-111 DTPAOC group, although both radiopharmaceuticals had the expected high affinity to the tumor. The T/N ratios in the In-111 DOTATOC group were also significantly higher than those in the In-111 DTPAOC group at 24 hr after injection. We conclude that In-111 DOTATOC showed lower clearance than In-111 DTPAOC in the rats bearing pancreatic tumors, although both of these radiopharmaceuticals showed expected high tumor uptake.

Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome.

PURPOSE: Subcutaneous (SC) octreotide acetate effectively relieves the diarrhea and flushing associated with carcinoid syndrome but requires long-term multiple injections daily. A microencapsulated long-acting formulation (LAR) of octreotide acetate has been developed for once-monthly intramuscular dosing. PATIENTS AND METHODS: A randomized trial compared double-blinded octreotide LAR at 10, 20, and 30 mg every 4 weeks with open-label SC octreotide every 8 hours for the treatment of carcinoid syndrome. Seventy-nine patients controlled with treatment of SC octreotide 0.3 to 0.9 mg/d whose symptoms returned during a washout period and who returned for at least the week 20 evaluation constituted the efficacy-assessable population. RESULTS: Complete or partial treatment success was comparable in each of the four arms of the study (SC, 58.3%; 10 mg, 66.7%; 20 mg, 71.4%; 30 mg, 61.9%; P> or =.72 for all pairwise comparisons). Control of stool frequency was similar in all treatment groups. Flushing episodes were best controlled in the 20-mg LAR and SC groups; the 10-mg LAR treatment was least effective in the control of flushing. Treatment was well tolerated by patients in all four groups. CONCLUSION: Once octreotide steady-state concentrations are achieved, octreotide LAR controls the symptoms of carcinoid syndrome at least as well as SC octreotide. A starting dose of 20 mg of octreotide LAR is recommended. Supplemental SC octreotide is needed for approximately 2 weeks after initiation of octreotide LAR treatment. Occasional rescue SC injections may be required for possibly 2 to 3 months until steady-state octreotide levels from the LAR formulation are achieved.

Pharmacokinetic-pharmacodynamic comparison of a novel multiligand somatostatin analog, SOM230, with octreotide in patients with acromegaly.

OBJECTIVE: Acromegaly is a serious hormonal disorder resulting from a pituitary adenoma causing excess growth hormone (GH) production. Somatostatin analogs such as octreotide have been the medical treatment of choice. SOM230, a novel somatostatin analog, was compared with octreotide with respect to pharmacokinetic (PK) profiles and inhibition of GH secretion in acromegalic patients. METHODS: In a double-blind, 3-period, crossover, proof-of-concept study, 12 patients with active acromegaly were randomized to single subcutaneous doses of SOM230 (100 and 250 microg) and octreotide (100 microg). Concentrations of SOM230, octreotide, and GH were determined at designated times after dosing and at baseline. The PK properties of SOM230 and octreotide and the relationship of PK with GH were investigated by a nonlinear mixed-effects modeling analysis. RESULTS: The apparent clearance for SOM230 is approximately half of that for octreotide (8.0 L/h versus 15.8 L/h). The elimination half-life for SOM230 is about 5 times longer than that for octreotide (11.8 hours versus 2.3 hours). The relationship between GH levels and plasma concentrations of SOM230 and octreotide is well described by a direct inhibitory model. The test drug concentration level at which half of the maximum drug effect is observed (EC50) is 46 and 553 pg/mL for octreotide and SOM230, respectively, with large interpatient variability (coefficients of variation, 164% and 65%, respectively), mainly attributable to the heterogeneous responses among patients. CONCLUSIONS: SOM230 demonstrates a lower clearance and longer half-life than octreotide, which compensates for the lower potency in GH inhibition. As a result of the lower interpatient variability for EC50 , SOM230 is expected to have a more uniform clinical GH inhibition than octreotide for acromegalic patients at a clinically effective dosing regimen.