PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
PAGE 26 (2017) Abstr 7119 [www.page-meeting.org/?abstract=7119]
Poster: Methodology - Covariate/Variability Models
Janet R. Wade (1), Rik Schoemaker (1), Lene Alifrangis (2)
(1) Occams, The Netherlands, (2) Symphogen A/S, Denmark
Objectives: Sym004 is a mixture of two synergistic full-length anti-EGFR antibodies (futuximab & modotuximab) that bind to 2 separate non-overlapping epitopes and inhibit the sustained growth of cancer cells.
Methods: PK data were from 136 patients from 2 trials in advanced solid tumours, SCCHN and mCRC (Sym004-01 and -02). Sym004 (0.4-18 mg/kg) was dosed by IV infusion weekly or every 2nd week or as a 9 mg/kg loading dose followed by 6 mg/kg weekly. Modelling was done in NONMEM v7.3 (FOCEI). Covariate model building was performed by evaluating each covariate one by one and then building a full final model with all covariates whose point estimates were outside the arbitrary range of 0.8 to 1.25 and whose 90% confidence intervals did not overlap the null value . Finally the structure of the base and final Sym004 Pop PK BLOCK(3) models were applied to each Sym004 constituent antibody.
Results: A 2-compartment model with linear and non-linear elimination and a priori inclusion of body weight on CL, VMAX, V1 and V2 was used. IIV was on CL, VMAX and V1. Correlations between the 3 IIV parameters were -0.277, 0.334 and 0.396. Residual variability comprised an additive plus proportional error model.
Conclusions: The final Sym004 pop PK covariate model structure depended upon the underlying statistical model structure despite low correlations between the IIV parameters . Effort should be made to define when a covariate effect is clinically meaningless (no effect), clinically irrelevant (small effect) and clinically important (larger effect) during the planning of analyses.