Abstract 3400
Background
ANAM, in advanced clinical development, showed benefits in cachectic patients with advanced non-small cell lung cancer (NSCLC). Typical values (TV) of ANAM PPK parameters, effects of demographic and physiopathologic covariates on PK parameters and their variability, and individual ANAM steady-state PK profiles in patients were assessed by PPK modeling.
Methods
Cachectic (body mass index <20 kg/m2 or ≥ 5% weight loss in prior 6 months) NSCLC patients (ROMANA 1 [NCT01387269; N = 477]) were randomized 2:1 to 100 mg once daily oral ANAM/placebo up to 12 weeks. Sparse blood samples were collected (day 43, 0.5–6 h post-treatment) in 70 patients consenting to the PK analysis. For modeling purposes, patients’ PK dataset was enriched with PK profiles from phase 1 (healthy subjects) and phase 2 studies. The PPK analysis included 243 PK profiles, 70 of which were from ROMANA 1. Non-linear mixed effect modeling with first-order conditional estimation with interaction was used for the PPK analysis. Correlations between ANAM PK parameters and continuous or categorical covariates were assessed by Spearman’s correlation coefficient or analysis of variance models, respectively. Individual steady-state ANAM PK profiles in the 70 patients were simulated by post-hoc empirical Bayes estimates of ANAM PK parameters, and used to assess ANAM exposure and elimination.
Results
The final model selected was a two-compartment model with first-order absorption and lag time, and no covariates as fixed effects. Patient vs healthy subject status was considered to cause no significant difference. TV of PPK parameters for absorption rate constant (5.39 h-1), lag time (0.24 h), volume of central (135 L) and peripheral (67.8 L) compartments, systemic clearance (CL/F, 49.5 L/h), and inter-compartmental clearance (8.8 L/h) were characterized by low relative standard errors (1.6%–15.9%). In patients, predicted ANAM peak plasma concentration, exposure (AUC0–24), and CL/F averaged 675 ng/mL, 2775 ng·h/mL, and 46.1 L/h, respectively.
Conclusions
The final PPK model described ANAM’s PK profile in healthy subjects and patients, and is suitable for predicting ANAM exposure in various clinical settings.
Clinical trial identification
NCT01387269.
Legal entity responsible for the study
Helsinn Therapeutics (U.S.), Inc.
Funding
Helsinn Therapeutics (U.S.), Inc.
Editorial Acknowledgement
Editorial and medical writing assistance was provided by Oana Draghiciu, PhD, CMPP, TRM Oncology, The Hague, The Netherlands, funded by Helsinn Healthcare (SA), Lugano, Switzerland.
Disclosure
A. Bernareggi: Employee: Helsinn Healthcare SA. S. Kaasa: Holds stocks: EIR Solution A/S. R.J.E. Skipworth: Research funding: Novartis; Previously unpaid member of advisory board: Helsinn. D. Currow: Unpaid member of advisory board: Helsinn Pharmaceuticals; Consultant to specialised therapeutics, Intellectual property payments: Mayne Pharma. All other authors have declared no conflicts of interest.