title: Establishing the Quantitative Relationship Between Lanreotide Autogel®, Chromogranin A, and Progression-Free Survival in Patients with Nonfunctioning Gastroenteropancreatic Neuroendocrine Tumors.
abstract: The objective of this work was to establish the quantitative relationship between Lanreotide Autogel® (LAN) on serum chromogranin A (CgA) and progression-free survival (PFS) in patients with nonfunctioning gastroenteropancreatic neuroendocrine tumors (GEP-NETs) through an integrated pharmacokinetic/pharmacodynamic (PK/PD) model. In CLARINET, a phase III, randomized, double-blind, placebo-controlled study, 204 patients received deep subcutaneous injections of LAN 120 mg (n = 101) or placebo (n = 103) every 4 weeks for 96 weeks. Data for 810 LAN and 1298 CgA serum samples (n = 632 placebo and n = 666 LAN) were used to develop a parametric time-to-event model to relate CgA levels and PFS (76 patients experienced disease progression: n = 49 placebo and n = 27 LAN). LAN serum profiles were described by a one-compartment disposition model. Absorption was characterized by two parallel pathways following first- and zero-order kinetics. As PFS data were considered informative dropouts, CgA and PFS responses were modeled jointly. The LAN-induced decrease in CgA levels was described by an inhibitory E MAX model. Patient age and target lesions at baseline were associated with an increment in baseline CgA. Weibull model distribution showed that decreases in CgA from baseline reduced the hazard of disease progression significantly (P < 0.001). Covariates of tumor location in the pancreas and tumor hepatic tumor load were associated with worse prognosis (P < 0.001). We established a semimechanistic PK/PD model to better understand the effect of LAN on a surrogate endpoint (serum CgA) and ultimately the clinical endpoint (PFS) in treatment-naive patients with nonfunctioning GEP-NETs.
authors.affiliation: Pharmacometrics & Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Irunlarrea 1, 31080, Pamplona, Spain.|IdiSNA Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Buil-Bruna
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: Pharmacometrics & Systems Pharmacology, 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; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism*; D053379:Chromogranin A / Q000008:administration & dosage / Q000378:metabolism*; D003692:Delayed-Action Preparations; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D005782:Gels; D006801:Humans; D007414:Intestinal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000378:metabolism*; D013004:Somatostatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality*
chemical_list: D000970:Antineoplastic Agents; D053379:Chromogranin A; D003692:Delayed-Action Preparations; D005782:Gels; D010456:Peptides, Cyclic; C060347:lanreotide; D013004:Somatostatin
keywords: chromogranin A; lanreotide; neuroendocrine tumors; population PK/PD; time-to-event analysis