Population pharmacokinetic (PK) analysis of lanreotide autogel/depot in the treatment of gastroenteropancreatic (GEP) neuroendocrine tumors (NETs): Pooled analysis of four clinical trials.

Abstract

397 Background: Lanreotide Autogel (Depot in US) has been shown in clinical trials to have antitumor effects and control symptoms associated with hormone hypersecretion in GEP NET patients. Objectives: To describe the PK of Lanreotide 60, 90, or 120 mg SC injections every 4 weeks in GEP NET patients, to quantify inter-patient variability (IPV) and to identify PK impacting patient characteristics. Methods: 1,541 serum concentrations were obtained from 290 patients and analysed simultaneously using the population approach with the software NONMEM version 7.2. The covariates evaluated included demographics, renal and hepatic function markers, and disease related information. Results: Serum profiles were described with a one-compartment disposition model and with an absorption process characterized by two parallel absorption pathways following first and zero order kinetics. The estimated apparent volume of distribution was 18.3 L. The estimated apparent total serum clearance for a typical 74 kg patient was 513 L/day. No covariate tested showed a statistically significant effect on the PK profile except body weight, which showed a moderate effect on clearance (clearance increased by 25% as weight increased by 30%). However, when comparing a subject with low weight (51 kg) to a subject with high weight (104 kg), their PK profiles were similar with a great degree of overlapping. Therefore, this weight effect on clearance was not considered clinically relevant. The magnitude of IPV was low for clearance (27%) and moderate for absorption constant (61%). However due to the lack of PK timepoints around the Cmax, a higher IPV was observed for volume of distribution (150%). Mean (SD) derived parameters AUC and Cmaxat steady-state were respectively 239 (64.8) ng.day/mL and 13.9 (7.44) ng/mL, showing moderate IPV in the PK profile. Conclusions: The PK of lanreotide Autogel/Depot was well characterized in GEP NET patients using two mechanisms of absorption. The IPVof the PK of lanreotide was moderate. Among all the patients characteristics tested, none were found clinically relevant to a potential dose adjustment in clinical practice.