Sandostatin LAR®: Pharmacokinetics, pharmacodynamics, efficacy, and tolerability in acromegalic patients

Abstract Sandostatin LAR® was developed by incorporating octreotide in microspheres of the biodegradable polymer poly( dl -lactide-coglycolide glucose). One hundred acromegalics, 85 of whom were known to be “responders” to octreotide (subcutaneous [SC] Sandostatin® 0.1 to 0.2 mg three times daily), as measured by mean 12-hour growth hormone (GH) serum concentrations below 5 μg/L, were switched after a washout period of at least 3 days to single doses of 3, 6, 9, 12, 10, 20, and 30 mg Sandostatin LAR®. Octreotide and GH serum concentrations were assessed hourly from 8 am to 8 pm , during screening, at baseline (after washout), and on days 1 (day of injection), 7, 14, 21, 28, 35, 42 (for doses of 3, 6, 9, and 12 mg), and 60 (for doses of 10, 20, and 30 mg). The pattern of octreotide release was similar for all doses tested. A rapid increase in octreotide serum concentrations was noted after the intramuscular (IM) injection of Sandostatin LAR®, with a peak occurring within 1 hour of injection and followed by a progressive decrease to low octreotide levels within 12 hours. On days 2 through 7, after single doses of Sandostatin LAR®, lower octreotide serum concentrations were recorded. Thereafter, an increase in the serum octreotide concentration occurred and dose-dependent plateau concentrations were observed between days 14 and 42, followed by a progressive decrease from day 42 onward. In the plateau phase (days 14 to 42), daily average octreotide plasma concentrations remained very stable over the 12-hour observation period, comparing well with those seen after continuous SC infusion. The peak level on day 1 (for the 10-, 20-, and 30-mg doses) was lower than plateau octreotide concentrations, and the area under the peak on the Sandostatin LAR® injection day was no greater than 0.5% of the total area under the curve ([AUC] 0 to 60 days). A dose-dependent increase in the octreotide maximum concentration and AUC occurred in the dose range of 10 to 30 mg. There is an almost linear relationship between plateau octreotide concentrations and the dose administered. Plateau octreotide concentrations were approximately 350 ng/L for the 10-mg dose, 750 for the 20-mg dose, and 1,300 for the 30-mg dose. No accumulation of octreotide was noted after repeated injections at 4-week intervals in 40 patients who received up to seven injections of Sandostatin LAR®. Steady-state octreotide serum concentrations were reached after multiple injections (three injections at 4-week intervals) and were higher by a factor of 1.6 in comparison to plateau octreotide levels noted after the first injection. Plateau octreotide concentrations lasting for a period of 20 to 30 days point to once-a-month dosing in long-term treatment. The pattern of GH secretion irrespective of dose showed an initial suppression for 8 to 12 hours, followed by a return to almost preinjection values on days 2, 3, and 7 after the first injection. From days 14 to 42, the maximum suppression of GH secretion was recorded for each dose tested. Reproducible and stable suppression of GH secretion was noted after single-dose administration of 10, 20, or 30 mg and repeated injections of 20, 30, or 40 mg Sandostatin LAR®, and this mirrored the consistent and stable octreotide concentration. A trend toward progressive suppression of GH secretion and insulin-like growth factor-I (IGF-I) serum concentrations was noted during long-term treatment (up to 35 weeks) with repeated (up to seven) IM injections of Sandostatin LAR®. Administered at 4-week intervals, the 20- and 30-mg doses provided a very good clinical control of acromegalic symptoms/signs in all patients, including the “partial responders” (with GH concentrations not suppressed to below 5 μg/L). The local tolerability was very good, with mild to moderate local pain on injection days. Systemic tolerability of Sandostatin LAR®, including gallstone formation, compared well with the SC treatment with Sandostatin®. As a result of the convenience of administration, very good acceptance, very stable and consistent octreotide serum concentrations in long-term treatment, and very good biological and clinical efficacy, it is expected that Sandostatin LAR® will become the medical treatment of choice in acromegalic patients.