The treatment of acromegalics with somatostatin analogs requires continuous sc infusion using pumps or several sc injections daily. Long-acting formulations (BIM-LA) of BIM 23014 (BIM) using delayed microcapsules may provide a more convenient form of therapy. Fourteen acromegalics whose GH secretion had not been normalized by transphenoidal surgery followed, in 10 cases, by pituitary radiotherapy (performed at least 2 yr before the study) were studied. Eight of these patients participated in an initial study of the pharmacokinetics of BIM-LA, after which a 6-month efficacy study was undertaken. The 8 patients in the pharmacokinetic study had an initial blood sample collected for measurements of plasma GH and insulin-like growth factor-I (IGF-I) levels before the im injection of 30 mg BIM-LA, and blood samples were subsequently taken 2, 4, 6, and 8 h after injection and then twice a week for a month. Plasma IGF-I levels were measured on days 4, 14, 20, and 30 after the injection. Assays of plasma GH, IGF-I, and BIM levels were performed by RIAs. The results showed that plasma GH levels were markedly reduced from 26.0 +/- 2.0 to 2.5 +/- 0.2 micrograms/L 2 h after BIM-LA injection and remained lower than 5 micrograms/mL for the 11 following days. Plasma GH levels increased to 5.5 +/- 1.2 micrograms/L on day 14 and returned to basal values 23 days after injection. Similarly, plasma IGF-I decreased from an initial level of 656 +/- 43 to 324 +/- 23 ng/mL on day 4 and remained close to the normal range for the following 10 days. Plasma BIM levels reached a peak 2 h after the injection (7.2 +/- 2.3 ng/mL) and remained higher than or close to 1 ng/mL until the 14th day after injection. This initial study showed that a single injection of 30 mg BIM-LA effectively suppressed GH and IGF-I secretion for at least 14 days, in accordance with the kinetics of the drug in plasma. Based on the results of this initial study, 30 mg BIM-LA were injected twice monthly for 6 months in all 14 patients. All of the subjects had a basal evaluation before treatment with BIM-LA and were then subjected to assessment of clinical, pituitary, and hormonal parameters. Patients were evaluated after 3 and 6 months of treatment on the same basis as that previously used when starting the BIM-LA therapy. Plasma BIM levels were measured monthly. Clinical signs of acromegaly improved during the treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
1 The aims of the study were to assess the pharmacokinetic parameters and the hormonal effects of the slow-release formulation of the somatostatin analogue (SR-L) in normal male volunteers. 2 Eight healthy males were studied. For the determination of basal values blood was sampled before the injection of vehicle and then every other hour for 8 h in order to measure plasma GH, prolactin (PRL), TSH, free thyroxin (fT4), insulin and glucagon levels. Plasma insulin-like growth factor 1 (IGF-1) levels were measured on a single sample. On day 1 of the study, 30 mg SR-L was administered intramuscularly. Blood was drawn just before injection and then every other hour for a period of 8 h. Thereafter, blood was sampled three times a week for 3 weeks in order to measure lanreotide, IGF-1, TSH, ff4 and PRL concentrations. Plasma GH was determined on days 6 and 11 of the study.3 Plasma lanreotide concentrations rose to 38.3 ± 4.1 ng ml-' 2 h following injection. The levels then progressively decreased, remaining above 1.5 ng ml-' until day 11 and reaching 0.92 ± 0.28 ng ml-' 2 weeks after injection. The apparent plasma half-life and mean residence time were 4.52 ± 0.50 and 5.48 ± 0.51 days respectively. 4 By comparison with the control day, plasma insulin concentrations only decreased 2 h following injection, whereas plasma glucagon did not change at any time. 5 Plasma TSH concentrations were significantly (P < 0.01) reduced from 2 h to day 4 following SR-L injection. ff4 concentrations dropped significantly (P < 0.01) from day 2 to day 4 but always remained within the normal adult range.6 Plasma GH concentrations were constantly below 0.2 ng ml-' whereas plasma IGF-l concentrations were significantly (P < 0.05) reduced from day 4 to day 14 following SR-L injection. No significant changes in plasma PRL levels were observed. 7 These results show that lanreotide administered in slow-release formulation to normal healthy males decreases transiently plasma insulin and TSH, and consecutively fT4 levels, without affecting either PRL or glucagon secretion. In contrast, SR-L reduces IGF-I levels (likely through a decrease in GH secretion) for at least 14 days. This indicates that SR-L could be injected every 14 days to decrease IGF-1 levels. 8 This slow-release formulation may be very convenient for the treatment of diseases for which a lowering of IGF-1 levels is essential, without side effects on glucose homeostasis and thyroid function.
No increase in toxicity was observed when subcutaneous lanreotide doses were escalated to 6 mg three times a day for 2 months. The highest doses seemed to maintain reduced serum IGF-1 levels; with the lowest doses, a "rebound" in serum IGF-1 levels was observed during treatment. Nevertheless, intermittent subcutaneous injections do not ensure constant serum drug concentrations over time.
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