title: Population Pharmacokinetic Analysis of Lanreotide Autogel/Depot in the Treatment of Neuroendocrine Tumors: Pooled Analysis of Four Clinical Trials.
abstract: OBJECTIVE
  Lanreotide Autogel (lanreotide Depot in the USA) has demonstrated anti-tumor activity and control of the symptoms associated with hormone hypersecretion in patients with neuroendocrine tumors. The objectives of this study were to describe the pharmacokinetics of lanreotide Autogel administered 4-weekly by deep subcutaneous injections of 60, 90, or 120 mg in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), to quantify the magnitude of inter-patient variability (IPV), and to identify those patient characteristics that impact on pharmacokinetics.
  
  
  METHODS
  Analyses were based on pooled data from clinical trials. A total of 1541 serum concentrations from 290 patients were analyzed simultaneously by the population approach using NONMEM version 7.2. Covariates evaluated included demographics, renal and hepatic function markers, and disease-related parameters.
  
  
  RESULTS
  Serum profiles were described by a one-compartment disposition model in which the absorption process was characterized by two parallel 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, representing a substantial difference in clearance in this population of patients with respect to healthy volunteers that could not be explained by any of the covariates tested. Body weight was the only covariate to show a statistically significant effect on the pharmacokinetic profile, but due to the overlap between the pharmacokinetic profiles of patients with lower or higher body weights the effect of body weight on clearance was not considered clinically relevant. The IPV was low for clearance (27%) and moderate to high for volume of distribution (150%) and the absorption constant (61%).
  
  
  CONCLUSIONS
  Using two mechanisms of absorption, the pharmacokinetics of lanreotide Autogel were well-described in patients with GEP-NET. None of the patient characteristics tested were of clinical relevance to potential dose adjustment in clinical practice.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Irunlarrea 1, 31080, Pamplona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Buil-Bruna
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Irunlarrea 1, 31080, Pamplona, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Garrido
authors.affiliation: Clinical Pharmacokinetics, Pharmacokinetics and Drug Metabolism, Ipsen Innovation, Les Ulis, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Dehez
authors.affiliation: Clinical Pharmacokinetics, Pharmacokinetics and Drug Metabolism, Ipsen Innovation, Les Ulis, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Manon
authors.affiliation: Clinical Pharmacokinetics, Pharmacokinetics and Drug Metabolism, Ipsen Innovation, Les Ulis, France.
authors.forename: Thi Xuan Quyen
authors.initials: TX
authors.lastname: Nguyen
authors.affiliation: Clinical Pharmacokinetics, Pharmacokinetics and Drug Metabolism, Ipsen Innovation, Les Ulis, France.
authors.forename: Edda L
authors.initials: EL
authors.lastname: Gomez-Panzani
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Irunlarrea 1, 31080, Pamplona, Spain. itroconiz@unav.es.|IdisNA, Navarra Institute for Health Research, Pamplona, Spain. itroconiz@unav.es.
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Trocóniz
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001835:Body Weight; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D006801:Humans; D007414:Intestinal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D018358:Neuroendocrine Tumors / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016032:Randomized Controlled Trials as Topic; D013004:Somatostatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D013274:Stomach Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D010456:Peptides, Cyclic; C060347:lanreotide; D013004:Somatostatin