Laura Fuhr, Nina Hanke, Thorsten Lehr
Clinical Pharmacy, Saarland University, Saarbruecken, Germany
Introduction: The direct oral anticoagulant dabigatran is an important alternative to warfarin, as it has predictable pharmacokinetics (PK), anticoagulant effects and can be applied in a fixed-dose regimen [1]. Since 2015, the antibody fragment idarucizumab is approved as specific dabigatran antidote, which enables quick and effective elimination of dabigatran and its anticoagulant action in case of heavy bleeding or emergency surgery [2]. Physiologically based pharmacokinetic (PBPK) modeling is a mathematical tool to investigate and predict the absorption, distribution, metabolism and excretion of small and large molecules throughout the body. In this study, PBPK modeling was applied to establish a PBPK model of idarucizumab and to investigate the influence of age, renal disease and ethnicity on the pharmacokinetics of idarucizumab.
Objectives:
- To develop a whole-body PBPK model of idarucizumab in healthy Caucasian adults
- To extend this model to other populations to accurately describe the impact of age, renal impairment and Japanese ethnicity on the PK of idarucizumab
Methods: The PBPK model was developed with PK-Sim® and MoBi® (Version 7.2.1) [3]. Drug-dependent parameters as well as plasma and urine concentration-time profiles of clinical studies were obtained from literature. First, a model of idarucizumab in healthy Caucasian adults was developed using 13 clinical studies (dose range 20 mg – 8000 mg, intravenous administration [4]). In a second step, changes in anatomy and physiology caused by aging, renal disease or a different ethnical background, such as body height, body weight or glomerular filtration rate (GFR), were implemented. For this model extension, 7 clinical studies of elderly or renally impaired individuals and 4 studies of Japanese subjects were used (dose range 1000 mg – 5000 mg, intravenous administration [5,6]). Finally, the model performance was evaluated by comparison of predicted to observed plasma concentration-time profiles, areas under the plasma concentration-time curve (AUC) and peak plasma concentrations (Cmax) of the external dataset.
Results: The final whole-body PBPK model of idarucizumab applies endosomal degradation of idarucizumab in the vascular endothelium, as well as glomerular filtration with reabsorption and subsequent degradation of idarucizumab in the cells of the proximal tubule. To enable the mechanistic modeling of these renal processes, the standard PK-Sim/MoBi® kidney structure was extended by a tubule compartment, according to a previously described approach by Balazki et al. [7]. The degradation of idarucizumab in the tubule cells was described using Michaelis-Menten kinetics. New insights into the metabolic processes in the tubule were gained, as a correlation between renal function and the degradation rate of idarucizumab in the proximal tubule could be shown. All predicted AUC and Cmax values are within two-fold of the observed values, demonstrating the good model performance. The geometric mean fold errors (GMFEs) between predicted and calculated AUC and Cmax values are 1.11 and 1.12, respectively. Comparison of predicted to observed plasma concentration-time points shows that 96% of all simulated concentrations lie within the boundaries of the two-fold acceptance limits.
Conclusion: The presented PBPK model of idarucizumab precisely describes and predicts the observed plasma concentration-time profiles and fraction excreted to urine over the full reported dosing range. The model can be applied to predict the PK of idarucizumab in healthy, elderly and renally impaired Caucasian individuals as well as in healthy Japanese subjects. As a future application, the established model will be coupled to a PBPK/PD model of dabigatran, to predict the effect of idarucizumab on the PK and clinical outcome of dabigatran administration and to support the treatment of patients with idarucizumab.
References:
[1] J. van Ryn et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost (2010) 103(6):1116-1127
[2] Boehringer Ingelheim Pharmaceuticals. Full prescribing information: Praxbind (2015)
[3] https://github.com/Open-Systems-Pharmacology
[4] S. Glund et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost (2015) 113(5): 943-951
[5] S. Glund et al. Effect of age and renal function on idarucizumab pharmacokinetics and idarucizumab-mediated reversal of dabigatran anticoagulant activity in a randomized, double-blind, crossover phase Ib study. Clin Pharmacokinet (2016) 56(1):41-54
[6] M. Yasaka et al. Safety, pharmacokinetics and pharmacodynamics of idarucizumab, a specific dabigatran reversal agent in healthy Japanese volunteers: a randomized study. Res Pract Thromb Haemost (2017) 1(2):943-951
[7] P. Balazki et al. A quantitative systems pharmacology kidney model of diabetes associated renal hyperfiltration and the effects of SGLT inhibitors. CPT Pharmacometrics Syst Pharmacol (2018) 7(12):788-797
Reference: PAGE 28 (2019) Abstr 8905 [www.page-meeting.org/?abstract=8905]
Poster: Drug/Disease Modelling - Absorption & PBPK