Xavier Nicolas (1), Nassim Djebli (1), Clemence Rauch (1), Aurélie Brunet (1), Fabrice Hurbin (1), Jean-Marie Martinez (1), David Fabre (1)
(1) Sanofi, Montpellier, France
Objectives: Alirocumab, a monoclonal antibody against PCSK9, significantly lowers LDL-C. The objective of this analysis was to develop and qualify a Pop PK/PD model for alirocumab based on pooled PK and PD data obtained from 13 Phase I/II/III clinical trials. We explored the potential relationships between the Pop PD parameters and demographic covariates, relevant co-administration, type of disease and relevant biologic constants.
Methods: From a dataset comprised of ~2800 patients (~14346 LDL-C concentration-time points), a two-staged approach was used and this Pop PK/PD model followed-on from the Pop PK model (part 1). Individual PK parameters from the Pop PK model were used to estimate alirocumab concentrations. An indirect response model with Hill coefficient, parameterised with increasing LDL-C elimination was developed to relate alirocumab concentrations with LDL-C values.
Results: The Pop PK/PD model allowed the characterisation of the PK/PD properties of alirocumab in the target population and estimation for each patient of LDL-C concentrations and derived PD parameters (ΔLDL-Cmax and ΔLDL-Ctrough). The relationship between several significant parameter-covariates was retained in the model, including 6 covariates on Emax, specifically time-varying total PCSK9, sex, age, weight, baseline free PCSK9 and statin co-administration. Nevertheless, this high number of covariates included in the model did not greatly impact model-derived PD parameters.
Conclusions: None of the covariates included in the model had a clinically significant impact on LDL-C reduction.
Reference: PAGE 25 () Abstr 5750 [www.page-meeting.org/?abstract=5750]
Poster: Drug/Disease modeling - Other topics