Population PK/PD modelling of the biomarker and progression free survival effects of Lanreotide Autogel in patients with non-functioning gastroenteropancreatic neuroendocrine tumors
Núria Buil-Bruna (1), Marion Dehez (2), Amandine Manon (2), Thi Xuan Quyen Nguyen (2), Iñaki F. Trocóniz (1)
(1) Pharmacometrics & Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona 31080, Spain, (2) Clinical Pharmacokinetics, Pharmacokinetics and Drug Metabolism, Ipsen Innovation, Les Ulis, France
Objectives: To develop a PK/PD model for the somatostatin analogue Lanreotide Autogel® (LA) in patients with non-functioning gastroenteropancreatic neuroendocrine tumours (GEP-NETs) establishing the relationship between serum concentrations of LA, biomarker Chromogranin A (CgA) serum levels, and progression free survival (PFS).
Methods: Data came from a phase III, randomized, double-blind, placebo-controlled study [1] conducted in 204 patients over 96 weeks where deep subcutaneous injections of LA 120 mg (n=101) or placebo (n=103) were administered every 4 weeks. The PK/PD model was established based on 810 serum samples of LA and 1298 (n=632 placebo and n=666 LA) serum samples of CgA; during the course of the study 76 patients experienced disease progression (n=49 placebo and n=27 LA).
The analyses were performed sequentially with NONMEM v7.2 [2]. First the PK model was selected and the corresponding empirical Bayes parameter estimates were used to describe the time course of CgA and its effects on PFS, the latter modelled as a time to event response variable.
Results: Serum profiles of LA 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.
Results shown PFS data had to be considered as informative drop-outs, and therefore CgA and PFS responses were modelled jointly. CgA levels were Box-Cox transformed for the analysis. Disease progression was characterized in the placebo group with a linear model (in Box-Cox scale). LA induced a decrease in CgA levels described by an inhibitory EMAX model. Inter-patient variability in the rate of disease progression and pharmacodynamic parameters was high (130%). C50 was estimated to be 7.8 ng/mL.
The Weibull model characterized the PFS hazard. A decrease on CgA with respect CgA0 reduced significantly the hazard (p<0.001). The covariates primary tumor location in pancreas, and baseline tumor hepatic load were associated with a higher risk (i.e., lower probability of PFS) (p<0.001).
Conclusions: A model linking in a mechanistic way drug exposure, biomarker and clinical endpoint could be established in patients with non-functioning GEP-NETs receiving LA. Our results indicate that there is a direct link between LA exposure and CgA levels, and that CgA levels in serum could be a good marker for the follow-up of the patients i.e. to monitor disease progression in this type of patients.
References:
[1] Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlácková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med (2014) 371: 224-233.
[2] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
