Population pharmacokinetic analysis of lanreotide Autogel in healthy subjects : evidence for injection interval of up to 2 months.

BACKGROUND AND OBJECTIVE: Lanreotide is a somatostatin analogue used for the treatment of acromegaly and neuroendocrine tumours. The objective of this study was to develop a pharmacokinetic model for the sustained-release formulation lanreotide Autogel after deep subcutaneous administration in healthy subjects, and to explore the potential effect of covariates, especially sex and dose. SUBJECTS AND METHODS: This was an open-label, single-centre, randomized, dose-ranging, parallel-group study, with a follow-up period of 4-7 months following drug administration in healthy subjects. Healthy Caucasian subjects aged 18-45 years were included. Subjects received a rapid intravenous bolus of 7 microg/kg of an immediate-release formulation of lanreotide (lanreotide IRF). After a 3-day washout period, participants were randomized to receive a single deep subcutaneous injection of lanreotide Autogel at a dose of 60, 90 or 120 mg. PHARMACOKINETIC AND STATISTICAL ANALYSIS: Blood samples for lanreotide determination were obtained during the first 12 hours after the intravenous bolus injection and during the 4- to 7-month follow-up period after deep subcutaneous administration of lanreotide Autogel. Data after intravenous and subcutaneous administration were fitted simultaneously using the population approach in NONMEM((R)) version VI software. The model was validated externally using data from patients with acromegaly. RESULTS: In total, 50 healthy subjects (24 women and 26 men) received a single intravenous dose of lanreotide IRF. Of these, 38 subjects (18 women and 20 men) received a single subcutaneous dose of lanreotide Autogel 3 days after intravenous lanreotide IRF. The disposition of lanreotide was described by a three-compartment open model. The estimates of the total volume of distribution and serum clearance were 15.1 L and 23.1 L/h, respectively. The estimates of interindividual variability were <40%. To evaluate lanreotide Autogel pharmacokinetics, the absorption rate was modelled to decrease exponentially as a function of the natural logarithm of time. The absolute bioavailability after deep subcutaneous administration of lanreotide Autogel was 63%. The rate of absorption and bioavailability of lanreotide Autogel were independent of the administered dose in the range from 60 to 120 mg, and no significant effect of covariates (sex, dose, age or bodyweight) was found (p > 0.05). CONCLUSIONS: Population analysis allows a full description of the disposition of lanreotide after rapid intravenous bolus administration of lanreotide IRF (7 microg/kg) and the pharmacokinetics of lanreotide Autogel after a single deep subcutaneous injection (60, 90 or 120 mg) in healthy subjects. The model-based simulations provide support for the feasibility of extending the dosing interval for lanreotide Autogel to 56 days when given at 120 mg. The absorption profile of lanreotide Autogel was independent of the dose and was not affected by sex.

Lanreotide autogel every 6 weeks compared with Lanreotide microparticles every 3 weeks in patients with well differentiated neuroendocrine tumors: a Phase III Study.

BACKGROUND: The noninferiority of a 6-week dosing schedule of lanreotide Autogel (Lan ATG) at a dose of 120 mg compared with a 3-week dosing schedule of lanreotide microparticles (Lan MP) at a dose of 60 mg was investigated in patients with neuroendocrine tumors (NET). METHODS: Patients who had sporadic, well differentiated NET with a low grade of malignancy were recruited for this open-label, Phase III, multicenter trial. Patients were randomized to receive either 3 deep subcutaneous injections of Lan ATG (120 mg, every 6 weeks) or 6 intramuscular injections of Lan MP (60 mg, every 3 weeks). Tumor markers, tumor size, and symptoms were assessed between baseline and Week 18. Success was classified as a response that ranged from disappearance to an increase <25% in tumor marker, tumor size, or symptom frequency. RESULTS: Sixty patients were randomized, and 46 patients completed the study. Both for tumor markers and for tumor size, Lan ATG was not inferior to Lan MP (55% and 59% of patients responded on tumor markers, respectively; 68% and 66% of patients responded on tumor size, respectively). There were too few symptomatic patients to compare carcinoid symptoms. Both treatments were tolerated well, and no safety concerns were identified. CONCLUSIONS: Lan ATG at a dose of 120 mg every 6 weeks was as effective for controlling NET as Lan MP at a dose of 60 mg every 3 weeks.