FP27-2 Population Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis of Lanreotide Depot in Acromegalic Patients: Clinical Evidence for a 8-week Extended Dosing Interval (EDI)

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP27-Pituitary: Acromegaly and Prolactinoma
Sunday, June 16, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 10:50 AM
Room 135 (Moscone Center)

Poster Board SUN-91
Marion Dehez*, Amandine Manon, Joaquim Ramis and Catherine Lesage
Ipsen, Les Ulis, France
Background: A previous population PK/PD model describing the relationship between lanreotide plasma concentrations after administration every 4 weeks and growth hormone (GH) reduction was developed. Model simulations predicted drug levels after a dose of 120 mg every 8 weeks that were anticipated to be sufficiently high to consider EDI from 4 to 8 weeks and still provide efficacy at steady state [1]. This was confirmed in 2 open-label phase 3 studies where lanreotide Depot 120 mg every 6 or 8 weeks effectively maintained GH control [2].

Objective: We developed a model describing the relationship between lanreotide plasma concentrations at 120 mg every 8 weeks and GH inhibition in acromegalic patients, and to compare this with the PD model obtained with standard regimens (60, 90, 120 mg every 4 wks) on the basis of the PD parameters (eg EC50).

Methods: This analysis included 111 patients treated with lanreotide Depot 120 mg every 8 weeks from 2 clinical studies. Different structural models describing the relationship between drug levels and GH inhibition and also residual error models were evaluated. Variability terms were tested on various parameters. The analysis was conducted using a population approach using NONMEM software v6.2.

Results: GH inhibition induced by lanreotide plasma concentration after administration of lanreotide Depot 120 mg every 8 weeks was well described by an inhibitory maximum effect model (Emax). The efficacy of lanreotide described by the Emax parameter was about 86% and the drug potency characterized by the EC50 parameter was 0.43 ng/mL. A low inter-individual variability (17%) was observed for Emax but higher variability (147%) was observed for EC50. The trough levels after single and repeat doses were 0.90 and 1.1 ng/mL, respectively, and were 2-fold higher than the estimated EC50. The median lanreotide plasma concentration associated with GH of <2.5 ng/mL was 1.1 ng/mL. A similar PD profile with comparable EC50 and Emaxbetween lanreotide Depot every 8 weeks and every 4 weeks was observed, showing GH inhibition was not schedule dependant.

Conclusion: This population PK/PD model further supports clinical data that the efficacy of lanreotide Depot 120 mg will be unaffected after extending its dosing interval from 4 to 8 weeks. Consequently, patients whose GH levels are controlled with lanreotide Depot 90 or 60 mg every 4 weeks may benefit from transferring to 120 mg every 6 or 8 weeks, respectively.

[1] Trocóniz IF, et al. Clinical Pharmacokinetics 2009;48(1):51-62.[2] Gomez-Panzani E et al. Research Reports in Endocrine Disorders. 2012:2 79-84

Disclosure: MD: Employee, Ipsen. AM: Employee, Ipsen. JR: Ad Hoc Consultant, Ipsen. CL: Employee, Ipsen.

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This analysis was carried out by Ipsen.