A Combined Pharmacometrics Analysis of Biomarker Distribution Under Treatment With Standard- or Low-Dose Rivaroxaban in Real-World Chinese Patients With Nonvalvular Atrial Fibrillation

Abstract

Background: The rivaroxaban dose regimen for patients with nonvalvular atrial fibrillation (NVAF) is complex in Asia. Given the high interindividual variability and the risk of bleeding caused by rivaroxaban in Asians, the influencing factors and the relationship between outlier biomarkers and bleeding events need exploration.Methods: The integrated pharmacokinetics (PK)/pharmacodynamics (PD) models were characterized based on rich PK/PD data from 304 healthy volunteers and sparse PD [anti-factor Xa activity (anti-Xa) and prothrombin (PT)] data from 223 patients with NVAF. The correlations between PD biomarkers and clinically relevant bleedings in 1 year were explored. The final integrated PK/PD model was used to evaluate the influence of dosage and individual covariates on PD parameters.Results: A two-compartment, linear model with sequential zero-order and first-order absorption was adopted. The dose-specific relative bioavailability (F1), diet status, creatinine clearance, and body mass index (BMI) improved the model fit. The apparent systemic clearance was 7.39 L/h, and the central and peripheral volumes were 10.9 and 50.9 L, respectively. The linear direct-effects model with shape factor plus the additive (and/or proportional) error model described the correlation between anti-Xa/PT and plasma concentration. Bodyweight, total cholesterol (TCHO), and diet status were selected as the covariates of the anti-Xa/PT model. Anti-Xa was more sensitive to the increase in rivaroxaban exposure compared with PT. An elevated bleeding tendency was seen with higher peak anti-Xa and PT. For a typical Chinese patient, the peak anti-Xa value (median (5%–95% PI)) of 20 and 15 mg were 309 ng/ml (139–597 ng/ml) and 296 ng/ml (138–604 ng/ml), both median values were within the expected range. For patients with CrCL 30–49 ml/min, the median peak anti-Xa with recommended 10 mg other than 15 mg were within the expected range.Conclusion: Fixed doses of rivaroxaban could be prescribed for patients with NVAF without adjustment for bodyweight, BMI, and TCHO. Randomized studies should be performed to evaluate the efficacy and safety of low-dose rivaroxaban in Chinese patients with NVAF.

Population Pharmacokinetics and Dose Optimization Based on Renal Function of Rivaroxaban in Thai Patients with Non-Valvular Atrial Fibrillation

“…The estimation of CL/F (4.19 L/h) in Thai DOAC-eligible AF patients was slightly lower than that reported in other ethnicities, including Caucasians (5.58-6.10 L/h) [20,37]. When compared to other Asian populations, the CL/F in this study is comparable to Japanese (4.72-4.73 L/h) [23,24] but lower than Chinese (5.03-7.39 L/h) [33,34,38]. The estimated V/F (37.5 L) was lower than that reported in other studies (40.3-79.7 L) [23,24,33,34,37].…”

“…The previous integrated PK/PD study of rivaroxaban in Chinese patients suggested that the median peak Anti-Xa level at a dose of 10 mg was within the expected range for patients with CrCL 30-49 mL/min but not at a dose of 15 mg [38]. As a result, dosage modification based on body weight is unnecessary [38]. Results from our simulations confirmed a lower rivaroxaban dose of 10 mg should be appropriate for patients with poor renal function (CrCl of 30-49 mL/min) regardless of body weight.…”

“…It has been determined that body size (i.e., lean body mass and body surface area) influences the PK characteristics of rivaroxaban [20,34,37,39]. One research involving healthy volunteers demonstrated that BMI influences the V/F of rivaroxaban [38]. Moreover, the results from previous studies showing that CrCl was the significant covariate influencing rivaroxaban CL/F, whereas other body size measurements alone were not found to significantly impact rivaroxaban CL/F [40,41].…”

“…The previous integrated PK/PD study of rivaroxaban in Chinese patients suggested that the median peak Anti-Xa level at a dose of 10 mg was within the expected range for patients with CrCL 30-49 mL/min but not at a dose of 15 mg [38]. As a result, dosage modification based on body weight is unnecessary [38].…”

Population Pharmacokinetics and Hemorrhagic Risk Analysis of Rivaroxaban in Elderly Chinese Patients With Nonvalvular Atrial Fibrillation

“…Pharmacokinetic characteristics may be related to bleeding risks. Rivaroxaban PPK models have been established in many diseases (including acute coronary syndrome (ACS), hip/knee replacement surgery, venous thrombosis, and nonvalvular atrial fibrillation) in previous studies, and some PPK studies have quantitatively evaluated the influence of genetics and body weight on the PK of rivaroxaban 18–21 . However, to date, little is known about PK characteristics regarding the optimal dosage of rivaroxaban in elderly Chinese patients with nonvalvular atrial fibrillation in a real clinical setting, and the relationship between rivaroxaban pharmacokinetics and hemorrhage risk in the population remains ambiguous.…”