Pharmacokinetics and population pharmacodynamic analysis of lanreotide autogel

Somatostatin analogs are the first-line medical therapy for acromegaly, and the treatment of this disease has been simplified by the development of extended-release formulations of these analogs. Lanreotide is a somatostatin analog that is available either as the microparticle formulation, requiring 7- to 14-day dosing, or as the aqueous Autogel formulation, requiring 28-day dosing. This study investigated the pharmacokinetics and pharmacodynamics of lanreotide. Patients with acromegaly were given 5 injections of lanreotide microparticles, 30 mg, followed by 3 injections of lanreotide Autogel, at doses of 60, 90, or 120 mg every 28 days. The study was extended to a further 12 injections of lanreotide Autogel with dose titration. A total of 144 patients were recruited; 130 received 3 injections of lanreotide Autogel, and 130 completed the extension phase. Average minimum lanreotide concentrations (C-min) at steady state were 1.949 +/- 0.619, 2.685 +/- 0.783, and 3.575 +/- 1.271 ng/mL for 60, 90, and 120 mg of lanreotide Autogel, respectively, showing a dose-proportional increase. Population pharmacodynamic analysis showed that the relationship between either formulation of lanreotide and serum growth hormone (GH) concentrations was best described using an inhibitory maximum response (E-max) model that allowed for the possibility of an incomplete inhibition of GH. Lanreotide elicited a maximum reduction in GH of 82%. Because patients were already being treated, baseline GH (E-0) was estimated, and the value of 8.63 ng/mL was in agreement with the inclusion criteria of GH 10 ng/mL or less. The effectiveness of treatment was demonstrated by the median serum concentration of lanreotide, 1.13 ng/mL, required to lower GH to 2.5 ng/mL or less. The serum concentration that elicited half of the E-max (EC50) was estimated as 0.206 ng/mL, showing a high sensitivity to lanreotide, with a predictably high interpatient variability of 200.75% reflecting the range of dosing regimens needed to control GH. (c) 2005 Elsevier Inc. All rights reserved.