Background/Objective: There is inconclusive evidence surrounding the pharmacokinetics (PK) of rivaroxaban in morbidly obese subjects with venous thromboembolism, which is associated with high rates of morbidity and mortality globally. The objective of the current study is to investigate the impact of obesity on rivaroxaban PK, using artificial intelligence-based computational methods.
Methods: GastroPlus® was used to develop a physiological-based pharmacokinetic (PBPK) model of rivaroxaban using previously published clinical trial data [1] after 20 mg tablet administered orally in subjects with normal body mass index (BMI) of 18.5-24.99 kg/m2. The model was calibrated against existing literature data of rivaroxaban through optimization of solubility, dissolution Z-factor, LogP, Peff, Fup, and liver clearance. The calibrated model was then used to perform Monte Carlo simulations to predict rivaroxaban PK profiles in 3000 subjects (BMI categories: 30-34.99; 35-39.99, and ≥40 kg/m2, presenting obese class 1, 2, and 3, respectively). Statistical analysis comparing Cmax , Tmax, AUC0-48, AUC0-inf in these three BMI groups vs. normal weight was carried out.
Results: A significant decrease of 20.9, 30.7, and 44.4% in the Cmax was observed in obese class 1, 2, and 3, respectively compared to normal weight subjects (p≤0.001). Similarly, a significant decrease of 6.7 and 13% in AUC0-48 was observed in obese class 2 and 3, respectively compared to normal weight subjects (p≤0.001). No significant differences were found for Tmax or AUC0-inf between obese groups and normal weight subjects.
Conclusion: The findings of this study suggest that obesity significantly alters the rivaroxaban PK profile, leading to a marked reduction in Cmax and AUC0-48, particularly in individuals with higher BMI categories. These changes may have important clinical implications for dosing strategies in obese patients to ensure optimal anticoagulant efficacy. Further clinical validation is warranted to refine dosing recommendations and improve therapeutic outcomes in this population.
Citations:
- Alalawneh M, ..et al. Pharmacokinetics of single-dose rivaroxaban under fed state in obese vs. non-obese subjects: An open-label controlled clinical trial (RIVOBESE-PK). Clin Transl Sci. 2024;17(6):e13853.