Population Pharmacokinetic Analysis of Lanreotide Autogel® in Healthy Subjects

Abstract

Abstractneuroendocrine tumours. The objective of this study was to develop a pharmacokinetic model for the sustainedrelease 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 µg/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 ® 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 µg/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. Backgroundmeters, the design included a rapid intravenous bolus injection of an immediate-release formulation of lanreotide (lanreotide IRF).

Lanreotide Depot: An Antineoplastic Treatment of Carcinoid or Neuroendocrine Tumors

“…In vivo release of lanreotide is governed by the intrinsic properties of self-assembly of the peptide itself and is most likely mediated by passive diffusion of lanreotide from the depot into the surrounding tissues, followed by the absorption to the bloodstream (Fig. 2a) [6, 29]. Indeed, PK studies confirmed the favorable PK profile expected based on the previous data.…”

Pharmacodynamic Modeling of the Effects of Lanreotide Autogel on Growth Hormone and Insulin‐Like Growth Factor 1

“…The procedure was repeated 500 times, and the 2.5th, 50th, and 97.5th percentiles of the controlled values were calculated from 500 simulations.Because a simulated‐based pharmacokinetic rationale for the feasibility of extending the dosing interval for lanreotide Autogel 120 mg to 56 days has been published, 3 the percentages of control of GH, IGF‐1, and GH + IGF‐1 were also calculated after 4 consecutive injections of lanreotide Autogel 120 mg every 56 days, using the simulation procedure described above. Values of C P were simulated using the population pharmacokinetic model for LA developed in healthy volunteers, which was externally validated with data from patients with acromegaly 3 . Model and parameters used to simulate C P are presented in supplementary material (Suppl.…”

“…The SSA lanreotide is currently available as an extended‐release formulation, lanreotide Autogel (LA) (marketed as Somatuline Depot in the United States), administered every 4 weeks (every 28 days). Recent pharmacokinetic data suggest the possibility of expanding such an interval up to 2 months (every 56 days) with the 120‐mg formulation 3 . There is considerable and recent published information supporting that LA is efficacious in controlling GH levels and/or normalizing IGF‐1 (IGF‐1 levels in the age‐adjusted range) in patients with acromegaly under different clinical scenarios 4 – 7 .…”

“…Recent pharmacokinetic data suggest the possibility of expanding such an interval up to 2 months (every 56 days) with the 120-mg formulation. 3 There is considerable and recent published information supporting that LA is efficacious in controlling GH levels and/or normalizing IGF-1 (IGF-1 levels in the ageadjusted range) in patients with acromegaly under different clinical scenarios. [4][5][6][7] However, to date, the relationship between drug exposure (using dose level or serum concentrations [C P ]) and clinical descriptors, such as the percentage of patients with controlled levels of GH, normalization of IGF-1 levels, or a combination of the two, has not been well characterized for any other SSA.…”

Lanreotide depot deep subcutaneous injection: a new method of delivery and its associated benefits

“…Minimum and maximum concentrations and area under the curve followed expected dose proportionality. Based on population pharmacokinetics, and software-assisted modeling of drug disposition, minimum effective levels of lanreotide were found with a dose of 120 mg 56 days after injection 27,32. With this information, the possibility of extending the interval between injections was suggested.…”