Jean-Marie Martinez (1), Aurélie Brunet (1), Fabrice Hurbin (1), A. Thomas DiCioccio (2), Clémence Rauch (1), Laura Lohan (3) and David Fabre (1)
(1) Sanofi, Montpellier, France, (2) Regeneron, Tarrytown, New York, (3) Faculty of Pharmacy, Montpellier, France
Objectives: Like many monoclonal antibodies (mAbs), the PK of alirocumab (an anti-PCSK9 mAb) is characterised by nonlinear, target-mediated PK (Target-Mediated Drug Disposition, TMDD): the elimination is partly mediated by binding to the target antigen. The Pop PK analysis reported here was developed to characterise the PK profile, identify factors affecting alirocumab PK and to compute individual patients’ PK parameters and exposures (i.e. AUC0-τ and Cmax).
Methods: From a dataset comprised of ~2800 patients (~13700 concentration-time points), a Michaelis-Menten approximation of the TMDD model was used to estimate PK parameters and exposures. The final model described here is a two-compartment model with a first order absorption process from the depot to the central compartment, parameterised in terms of the absorption constant (Ka, h-1). A linear process (CLL, L/h) and a non-linear process, represented by the Michaelis-Menten parameters Vm (mg.h/L) and Km (mg/L), were used to describe the elimination from the central compartment. Both compartments were represented by a distribution volume (V2 +V3) linked by an inter-compartmental clearance Q. A lag time and the bioavailability factor F completed the set of fixed effect model parameters θs.
Results: The Pop PK model enabled estimation of alirocumab PK properties and individual exposures. The model also allowed for identification of covariates that explained inter-individual variability of alirocumab treatment: CLL was related to body weight and co-administration of statins, Km was related to free time-varying PCSK9 serum levels and V3 was related to age.
Conclusions: The PK of alirocumab is best described as non-linear, with target-mediated clearance, although the deviation from linearity is modest. Alirocumab PK parameters were estimated using the Pop PK model, with 4 main covariates identified that impact alirocumab PK. The model was used to predict alirocumab concentrations which were subsequently used to build a Pop PK/PD model (part 2).
Reference: PAGE 25 () Abstr 5855 [www.page-meeting.org/?abstract=5855]
Poster: Drug/Disease modeling - Other topics