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.

Evaluation of the treatment of thyrotropin-secreting pituitary adenomas with a slow release formulation of the somatostatin analog lanreotide.

Somatostatin analogs have been shown to be effective for the treatment of TSH-secreting pituitary adenomas. However, their use in this indication is limited by the fact that available analogs require several daily sc injections. The present study was performed to evaluate the effects of a slow release formulation of the somatostatin analog lanreotide (SR-L) on both hormone secretion and tumor size and to assess the tolerance in a series of thyrotropinomas treated for 6 months. Eighteen patients with hyperthyroidism related to a TSH-secreting pituitary adenoma, evidenced by pituitary magnetic resonance imaging, were studied. After a basal assessment, each patient received 30 mg SR-L, im, every 14 days for 1 month. Then, according to the free T3 (fT3) plasma level measured, 9 of 18 patients were injected twice monthly, and 7 of 18 patients received SR-L every 10 days for 5 additional months. One patient was dismissed from the study in month 1 of the study for side-effects and another in month 3 for noncompliance to the protocol. Clinical and biological evaluations (plasma TSH, free alpha-subunit, fT4, fT3, and lanreotide levels) were performed before and in months 1, 3, and 6 of treatment. Pituitary magnetic resonance imaging and gallbladder ultrasonography were performed both at entry and at the end of the study. Clinical signs of hyperthyroidism improved within 1 month in all 16 evaluable patients. Mean (+/- SEM) plasma lanreotide levels reached 1.11 +/- 0.43 and 1.69 +/- 0.65 ng/mL in month 3 using 2 and 3 injections/month, respectively, then remained stable until the end of the study. During therapy, the plasma TSH level decreased from 2.72 +/- 0.32 to 1.89 +/-0.27 mU/L (P < 0.01), with parallel significant changes in free alpha-subunit. During the same period, plasma fT4 and fT3 levels decreased from 37.9 +/- 2.9 to 19.7 +/- 2.3 pmol/L (P < 0.01) and from 14.6 +/- 1.1 to 8.3 +/- 0.8 pmol/L (P < 0.01), respectively. No statistically significant change in mean adenoma size was observed after 6 months of treatment. Side-effects, including pain at the injection point, abdominal cramps, and diarrhea, were mild and transient and did not lead to interruption of the treatment. No gallstones occurred during the study. SR-L appears to be able to suppress clinical signs of hyperthyroidism in our series of patients with TSH-secreting pituitary adenomas. The analog also reduces plasma TSH and thyroid hormone levels, which were normalized in 13 of 16 cases. The effect was maintained throughout the treatment using 2 or 3 SR-L injections monthly without any problem of tolerance. We conclude that SR-L is a safe and effective treatment of thyrotropinomas and avoids the drawbacks of the modes of administration of other somatostatin analogs, given three times daily.

Treatment of carcinoid syndrome: a prospective crossover evaluation of lanreotide versus octreotide in terms of efficacy, patient acceptability, and tolerance.

BACKGROUND: The somatostatin analogues lanreotide and octreotide have previously been shown to be effective in controlling flushing and diarrhea in patients with carcinoid syndrome. As lanreotide requires injection only every 10 days, compared with twice-daily injections of octreotide, a direct comparison between these two treatments in terms of patient acceptability, patient preference, and efficacy in controlling symptoms was performed in patients with carcinoid syndrome. METHODS: Thirty-three patients with carcinoid syndrome were included in an open, multicenter, crossover study. Half of the patients received octreotide 200 microg subcutaneously twice or thrice daily for 1 month followed by lanreotide 30 mg intramuscularly every 10 days for 1 month, while the other half commenced with lanreotide followed by octreotide in a similar fashion. Quality-of-life assessments were performed at each visit and patient preference for one of the two treatments evaluated. The number and intensity of flushing episodes and bowel movements, urinary 5-hydroxyindoleacetic acid (5HIAA) levels, and plasma serotonin levels were recorded. RESULTS: No significant differences were found between lanreotide and octreotide in terms of quality of life. The majority of patients (68%) preferred lanreotide (P = 0.03), largely due to its simplified mode of administration. Disappearance or improvement in flushes occurred in 53.8% of patients (14 of 26) while on lanreotide and in 68% (17 of 25) on octreotide. A disappearance or improvement of diarrhea in 45.4% (10 of 22) on lanreotide, compared with 50% (11 of 22) on octreotide, was also observed. Lanreotide and octreotide were equally effective in reducing urinary 5HIAA levels and plasma serotonin levels. Both treatments were well tolerated, with mild symptoms of abdominal pain and nausea observed in 29% and 14% receiving octreotide and lanreotide, respectively. CONCLUSIONS: Lanreotide and octreotide are equally efficacious in terms of symptom control and reduction in tumor cell markers for patients with carcinoid syndrome. Due to its simplified mode of administration, most patients prefer treatment with lanreotide.

Effects of lanreotide, a somatostatin analogue, on postprandial gastric functions and biliopancreatic secretions in humans.

AIMS: Lanreotide is a novel synthetic somatostatin analogue. A long-acting formulation of lanreotide has been shown to be effective for the treatment of gastroentero-pancreatic hormone-producing tumours but effects on postprandial digestive and absorptive functions remain obscure. The aim of the present study was to evaluate the effects of intravenous lanreotide on gastric and biliopancreatic secretions in man as well as the absorption of nutrients and the duodeno-caecal transit time after ingestion of an homogenized meal (500 kcal, 55% carbohydrates, 15% proteins, 30% lipids). METHODS: Eight healthy male volunteers were studied on two occasions within a 2 weeks interval, using a perfusion method. They received in single-blind and random order continuous i.v. infusion of either placebo or lanreotide (100 micrograms h-t after a bolus of 100 micrograms 15 min before the beginning of the study). RESULTS: Lanreotide significantly decreased gastric acid secretion (90%) for the initial 3 h period. Gastric emptying was not significantly modified by lanreotide infusion. Compared with placebo, lanreotide almost completely abolished both bile salts and lipase responses to the meal. It largely increased the duodeno-caecal transit time and decreased significantly the duodenal absorption of carbohydrates and triglycerides. CONCLUSIONS: Since lanreotide has powerful effects on gastrointestinal functions, it could be useful in the prevention or in the treatment of pancreatic and bowel fistulas as well as short bowel syndrome.

Intramuscular injections of slow-release lanreotide (BIM 23014) in acromegalic patients previously treated with continuous subcutaneous infusion of octreotide (SMS 201-995).

Nine acromegalic patients (five females and four males), mean age 50 +/- 4 years, presented macroadenomas (N = 7), microadenoma (N = 1) or normal computed tomography scans (N = 1). Patients were treated with continuous subcutaneous infusion of octreotide (range 200-600 micrograms/day). Following a washout period of 7 days, the patients were injected im with 30 mg slow-release lanreotide every 10 days for the first month and then twice monthly. In case of elevated growth hormone (GH) levels at 3 months, the patients were injected every 10 days for the next three months. Plasma GH and insulin-like growth factor I (IGH-I) decreased in all patients during octreotide treatment. After 6 months of octreotide treatment, seven patients were considered as well controlled (mean 8 h GH < 5 micrograms/l, IGF-I normal) whereas in two patients the mean 8-h GH and/or IGF-I levels remained increased. Serum GH and IGH-I increased after octreotide withdrawal. In one patient, serum GH and IGF-I increased during slow-release lanreotide administration and injections were stopped after 45 days. After 3 months of lanreotide, three patients were well controlled while in five patients GH or IGF-I levels were not normalized. At 6 months, five patients were injected twice monthly and three patients had one injection every 10 days. Six patients were well controlled and in two patients the mean 8-h GH level remained increased. The pituitary tumor volume decreased by 20-30% in two patients during octreotide, as well as in one other during slow-release lanreotide therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Slow release lanreotide treatment in acromegalic patients previously normalized by octreotide.

Several clinical studies reported the efficacy of the long-acting SRIH analog, octreotide (Octreotide, Sandoz) in the treatment of acromegaly. Recently, another SRIH analog (BIM 23014, Ipsen Biotech) was shown to decrease plasma GH levels in acromegalic patients. The recent availability of a long-acting formulation of BIM 23014 [slow release (SR) lanreotide] could avoid the inconveniences associated with either repeated sc injections or continuous sc infusions. In this study, we compared the clinical and biochemical efficacies of both drugs in a cohort of 19 acromegalic patients, considered initially as responsive to octreotide and sequentially treated with octreotide (3 sc injections of 100-200 micrograms/day) for 12 months and with SR lanreotide (30 mg, im, every 10 or 14 days) for 6 months. Before octreotide treatment, baseline plasma GH (mean +/- SE of 8 hourly samplings) was 29.0 +/- 10.0 micrograms/L and was lowered to 3.2 +/- .2 micrograms/L during the first 7 h after the first 100-micrograms sc octreotide administration. After 12 months of treatment with octreotide, 14 of 19 patients (74%) were considered normalized, as their mean individual GH profiles and insulin-like growth factor-I (IGF-I) values were within the normal range. After octreotide withdrawal for 1 week, plasma GH and IGF-I levels rose to 18.3 +/- 4.8 and 4.1 +/- 0.4 U/mL, respectively. The first 30-mg SR lanreotide im injection produced an acute suppression of plasma GH levels (mean GH value during the 7 h after the injection, 3.0 +/- 0.4 micrograms/L), not different from results previously observed after the first octreotide injection. After 3 months of treatment with 30 mg SR lanreotide every 14 days, normalization of baseline GH and IGF1 levels was achieved in 6 of 19 patients. Ten patients, who did not achieve normal GH levels, subsequently received a 30-mg SR lanreotide injection every 10 days. Among them, normalization of GH and IGF-I levels occurred in 7 of 10 patients after 3 months of such a regimen. After 6 months of SR lanreotide treatment, 13 of 19 patients (68%) were considered normalized, with mean GH and IGF-I values, respectively, of 3.1 +/- 0.4 micrograms/L and 1.5 +/- 0.1 U/mL. The overall tolerance of both drugs (glucose homeostasis and gallstone formation) was similar.(ABSTRACT TRUNCATED AT 400 WORDS)

Long-term treatment of acromegaly with the slow-release somatostatin analogue lanreotide.

Thirteen patients with active acromegaly despite previous surgery were treated with 30 mg lanreotide im twice a month for 9 months. In 10 subjects the treatment continued to 19 months. GH serum levels of all patients decreased significantly from an initial value of 32.0 (29.4) micrograms/l [median (standard error of median)] to 10.0 (3.6) and 19.1 (5.7) after 3 and 9 months of treatment, respectively. In the 10 patients with the treatment longer than one year the decrease in GH was from 46.8 (29.4) micrograms/l to 12.5 (5.0) and 16.1 (5.3) after 13 and 19 months, respectively. IGF-I serum levels decreased significantly from 1193 (73) micrograms/l to 782 (99) and 621 (103) after 3 and 9 months, respectively, and were normalized in 3 patients. In the 10 patients treated for longer than one year, levels decreased significantly from 1318 (74) micrograms/l to 653 (170) and 742 (180) after 13 and 19 months, respectively. IGF BP-3 levels were reduced to the normal range in 6 patients and decreased from 8.7 (1.5) mg/l to 6.4 (0.8) and to 5.4 (1.0) after 3 and 9 months, respectively. In the patients with the 19 months treatment the decrease was from 9.3 (1.6 mg/l to 3.9 (0.9) and 4.8 (0.9) after 13 and 19 months, respectively. The IGF BP-3 to IFG I ratio increased in 7 patients. This elevation significantly correlated with the decrease in bioassayable somatomedin. Prolactin serum levels fell in all patients with increased prolactin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of a slow-release formulation of the new somatostatin analogue lanreotide in TSH-secreting pituitary adenomas.

OBJECTIVE: Somatostatin analogues have been proposed for the treatment of thyrotrophinomas. However, this treatment requires several s.c. injections a day to be effective. The present study had the following aims: (i) appraisal of the efficacy of a single dose of two somatostatin analogues (lanreotide and octreotide) to acutely inhibit TSH secretion of TSH-secreting pituitary adenomas; (ii) assessment of the efficacy of a single injection of a slow release formulation of lanreotide (SR-L) in reducing TSH and thyroid hormone secretions in the same cases; and (iii) evaluation of the effects of SR-L used for 3-6 months on hormone secretion and tumour size. PATIENTS: Four patients with hyperthyroidism linked to a TSH-secreting pituitary adenoma found on pituitary magnetic resonance imaging (MRI) and subsequently proved by immunohistochemistry were studied. METHODS: In the first step of the study the patients received in a random order, vehicle, 150 micrograms octreotide and 500 micrograms lanreotide as a single s.c. injection. Measurements of plasma TSH, free T4 (fT4), free T3 (fT3) and free alpha subunit (fAS) levels were carried out before injection and then every other hour for 8 hours. In the second part of the study, after a basal blood sample (0800 h), each patient received 30 mg lanreotide as an i.m. injection of SR-L. Blood was sampled 2 hours later and then three times a week for 3 weeks in order to measure plasma TSH, fT4, fT3 and lanreotide levels using radioimmunoassays. The patients then received one SR-L injection twice or in one case three times a month for 3-6 months. Plasma TSH, fT4 and fT3 levels were measured monthly and a pituitary MRI was performed at the end of the treatment with SR-L. RESULTS: 500 micrograms lanreotide acutely reduced plasma TSH and fAS levels to the same extent as 150 micrograms octreotide. Two hours after a single i.m. injection of SR-L plasma lanreotide levels reached 7.8 +/- 0.6 micrograms/l and then progressively decreased, being 1.8 +/- 0.2 microgram/l on day 2 and 1.1 +/- 0.3 microgram/l on day 14 after the injection. Plasma TSH level decreased from basal value (mean +/- SEM 4.4 +/- 1.2 mlU/l) within 2 hours (2.5 +/- 0.8 mlU/l) and further declined to 0.8 +/- 0.2 ml/Ul on day 2 following the injection. Depending on the patient, plasma TSH levels were reduced for a period of 6-15 days. Plasma fT4, fT3 levels were normalized on day 2 and remained in the normal range for a period of time of 9-20 days. During long-term treatment, abdominal cramps and diarrhoea appeared, leading to interruption of the treatment in one patient. The treatment was well tolerated in the other three patients. Plasma TSH and thyroid hormone levels progressively decreased during the treatment. No change in adenoma volume was observed after 3-6 months of therapy. CONCLUSIONS: This study shows that (i) lanreotide is able to inhibit acutely TSH secretion in thyrotrophinomas and that a single s.c. injection of 500 micrograms lanreotide is as effective as 150 micrograms octreotide; (ii) SR-L appears to be able to reduce plasma TSH and to normalize fT4 and fT3 levels for 9-20 days in patients with thyrotrophinomas; (iii) this effect is maintained throughout the treatment using two or three SR-L injections monthly for months. These results suggest that SR-L could be used as a treatment of thyrotrophinomas and avoids the drawbacks of the modes of administration of other somatostatin analogues used in such cases.

[Treatment of acromegaly with a new slow release somatostatin analog, lanreotide]. / Traitement de l'acromégalie par un nouvel analogue de la somatostatine, le lanréotide à action prolongée.

Treatment of Acromegaly has been improved by the development of the somatostatin analogs characterized by an increased specificity and longer duration of action. One of these analogs-Lanreotide- (Somatuline) is supplied under a slow release formulation and does not require several daily injections like other analogs presently available. The clinical pharmacodynamic studies that have been conducted in healthy and acromegalic patients show that the i.m. injection of a single dose of this slow-release formulation leads to a significant decrease of the plasma GH and IGF-1 levels. This effect lasts at least 14 days. The Lanreotide slow-release formulation has been used to treat 123 acromegalic patients who presented with a still evolutive disease after conventional therapy. The product was given at a 30 mg-dose every 10 or 14 days during a 3-to 24-month period. This treatment led to a reduction of the symptoms and to a decrease of GH hypersecretion. GH and IGF-1 levels have been normalized respectively in 46% and 32% of the patients. The observed results allow to conclude to an immediate efficacy of the treatment (without escape sign). The adverse drug events are minor and transitory. The antitumor effects are modest and inconstant. The slow release formulation seems to provide the patients with a better quality of life, as compared to the several daily injections.

[Treatment of acromegaly with sustained-release lanreotide. A new somatostatin analog]. / Traitement de l'acromégalie par une forme à libération prolongée du lanréotide. Un nouvel analogue de la somatostatine.

The recovery of acromegaly is not obtained in about 50 percent of cases treated with radiotherapy and/or transsphenoidal surgery. Somatostatin analogs prescribed in such cases are effective but need either several subcutaneous injections a day or continuous infusions with pumps. Long-acting formulations of the new somatostatin analog lanreotide should avoid such drawbacks. Nine acromegalics, not cured by pituitary surgery (associated with radiotherapy in 7) received on IM injection of a long acting formulation of lanreotide twice a month for one year. Basal evaluation included: clinical examination, routine analyses, gall bladder ultrasonography, hormonal investigation of pituitary function including GH and IgF-1 measurements, visual field evaluation and pituitary scanning. A similar evaluation was performed on months 6 and 12 of treatment. The clinical symptoms of acromegaly progressively improved during therapy. Plasma GH levels decreased significantly (P < 0.01) from 24.2 +/- 2.1 to 9.3 +/- 1.2, 6.4 +/- 1.4 and 7.9 +/- 1.1 micrograms/l on months 3, 6 and 12, respectively. Plasma IgF-1 levels were normalized, decreasing from 676 +/- 40 to 331 +/- 30, 350 +/- 36, and 317 +/- 29 ng/ml on months 3, 6 and 12, respectively. Plasma lanreotide levels remained stable throughout the treatment. Side-effects included slight and transient diarrhoea and abdominal cramps which disappeared after 6 months of treatment. No gallstones appeared during treatment. These results show that one injection, twice a month, of a long-acting formulation containing 30 mg lanreotide is able to control the evolutivity of acromegalies not cured by pituitary radiotherapy and/or transsphenoidal surgery. Such formulations are well tolerated and avoid the drawbacks of either several subcutaneous injections a day or continuous infusions of somatostatin analogs.