Alan Faraj1, Judi Møss2, Kristoffer Winther Balling1, Malte Selch Larsen1
1Pharmacometrics Novo Nordisk A/S, 2Clinical Pharmacology Novo Nordisk A/S
Objectives: Concizumab (CZM) is a humanized recombinant monoclonal antibody targeting tissue factor pathway inhibitor (TFPI) and is in development as a subcutaneous treatment alternative for prevention of bleeds, including long-term prophylaxis in patients with haemophilia A and B (HA/HB), with and without inhibitors (HAwI/HBwI). This work was conducted to characterize the relationship between CZM exposure and biomarkers such as free TFPI (not in complex with concizumab), thrombin peak from ex vivo thrombin generation assay, and bleeding events. Methods: PK, PD (free TFPI and thrombin peak) and bleeding event data from eight clinical trials (phase 1-3) with intravenous and subcutaneous administration were pooled and used for model building. Based on previous work [1], a target-mediated drug disposition (TMDD [2]) was used to describe the PK of CZM. Covariate effects were estimated using the full model approach [3] and tested for statistical significance (p=0.001) in a backward deletion procedure. Direct sigmoidal Emax models were used to characterize the exposure-response for free TFPI and thrombin peak levels whereas a repeated time-to-event approach was used to link CZM concentrations and occurrence of bleeding events over time. Inter-occasional variability was included to account for inter-dose variability in PK of CZM to reduce risk of biasing characterization of the PK-bleeding event relationship. Covariate effects for the exposure-response models were explored using the stepwise-covariate-modeling approach [4] including a forward (p=0.01) and a backward step (p=0.001). Results: The final model was a two-compartment model with transit for delayed absorption and combined linear and non-linear elimination (quasi steady state approximated TMDD [2]). Inter-individual variability (IIV, expressed as coefficient of variation [CV]) was included on total capacity of TMDD (Rtot [26%]). In addition to allometry with fixed exponents on the disposition parameters, bodyweight was the most important covariate and was found to increase Rtot. Further, a phase 3 covariate was found to increase the concentration for 50% saturation of TMDD (Km). Free TFPI was not found as a significant covariate for the PK of CZM, indicating that it may be the endothelial-bound TFPI that is the driver of the non-linear elimination. Direct Emax models described the decrease and increase in TFPI and thrombin peak with increasing CZM exposure, respectively, with most of the PK observations sampled at Emax. IIV was included on baseline levels (E0), Emax and EC50 (31, 50, 21%) and on E0 and EC50 (8 and 52%) for the thrombin peak and free TFPI models, respectively. No covariates were included for free TFPI. For thrombin peak, adolescents were found to have a lower Emax whereas HAwI and HBwI subjects had higher Emax. In addition, HAwI, HB and HBwI subjects were found to have a lower E0. These covariate effects are not expected to impact clinical efficacy. The final PK-bleeding event model was described with a Gompertz baseline hazard function and the effect of CZM exposure was described by an inhibitory Emax(fixed to 1) model on the hazard (EC50=92.8 ng/ml). HAwI and HBwI were found to reduce the baseline hazard. IIV was supported for the baseline hazard (99%) and EC50 (372%). The final models described the data well based on visual predictive checks. Conclusions: The exposure-response analyses showed that the CZM dosing regimen maintains plasma concentrations close to Emax plateau according to the exposure-response model. The final models developed in this work described the data well and was considered appropriate for clinical trial simulations to support the proposed CZM dosing regimen.
[1] Rose, TH. et al, Blood, 2020 [2] Gibiansky, L. et al, JPKPD, 2008 [3] Hu, C. et al, Pharm Stat, 2011;10(1):14-26 [4] Keizer, R. J., Karlsson, M. O. & Hooker, A. Modeling and Simulation Workbench for NONMEM: Tutorial on Pirana, PsN, and Xpose. CPT Pharmacomet. Syst. Pharmacol. 2 (2013)
Reference: PAGE 33 (2025) Abstr 11430 [www.page-meeting.org/?abstract=11430]
Poster: Drug/Disease Modelling - Other Topics