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

Abstract

Rivaroxaban is a popular direct factor Xa inhibitor used for anticoagulation therapy in patients with nonvalvular atrial fibrillation (NVAF). The aim of this study was to establish a population pharmacokinetic (PPK) model for rivaroxaban in elderly Chinese patients with nonvalvular atrial fibrillation, evaluate precision dosing regimens, and analyze hemorrhagic risk after rivaroxaban treatment. A 1-compartment population PK model with estimated glomerular filtration rate (eGFR), total bilirubin (TBIL), and ABCB1 rs1045642 as major covariates for apparent clearance was developed using the nonlinear mixed-effects model (NONMEM). A Monte Carlo simulation was performed to evaluate various dosing schemes and different levels of covariates for the target range of therapeutic drug-monitoring concentrations (C max,ss and C min,ss ). The exposure to rivaroxaban was simulated and assessed through hemorrhagic risk evaluation. The results showed that the average probability of target attainment (PTA) for optimal dosing regimens with different covariate levels for the targeted C max,ss and C min,ss were 29.35% to 31.3% and 64.91% to 65.8%, respectively. A dosage of 10 mg of rivaroxaban in elderly Chinese patients with normal renal and liver function was appropriate. The area under the concentration-time curve estimated over 24 hours with precision dosing at steady state (AUC 24,ss ) was statistically significantly associated with an increased risk of bleeding events (OR 1.0006, 95%CI 1.0003 to 1.001, P < .0001), and the bleeding risk increased by 1.82-fold for every 1000 μg*h/L increase in AUC 24,ss . A lower dose is recommended for elderly patients with renal impairment to avoid overexposure and bleeding events. The PPK model could inform individualized dosing for elderly Chinese patients with nonvalvular atrial fibrillation receiving rivaroxaban anticoagulation therapy.

Is a Lower Dose of Rivaroxaban Required for Asians? A Systematic Review of a Population Pharmacokinetics and Pharmacodynamics Analysis of Rivaroxaban

“…All 24 studies included were prospective, and each of their characteristics is listed in Table 1 . Two studies involved healthy adult subjects [ 19 , 20 ], nineteen studies included adult patients [ 18 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ], and three studies were conducted on pediatric patients [ 39 , 40 , 41 ]. Ten studies (41.7%) were from the Asians, including Japanese ( n = 4), Chinese ( n = 4), Thai ( n = 1), and Iranian population ( n = 1), the study cohorts of which were almost all patients with NVAF [ 18 , 20 , 25 , 26 , 30 , 34 , 35 , 36 , 37 , 38 ].…”

“…Two studies involved healthy adult subjects [ 19 , 20 ], nineteen studies included adult patients [ 18 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ], and three studies were conducted on pediatric patients [ 39 , 40 , 41 ]. Ten studies (41.7%) were from the Asians, including Japanese ( n = 4), Chinese ( n = 4), Thai ( n = 1), and Iranian population ( n = 1), the study cohorts of which were almost all patients with NVAF [ 18 , 20 , 25 , 26 , 30 , 34 , 35 , 36 , 37 , 38 ]. Fourteen studies were conducted on population of multiple ethnicities, which were all or predominantly Caucasians [ 19 , 21 , 22 , 23 , 24 , 27 , 28 , 29 , 31 , 32 ,…”

“…Fourteen studies were conducted on population of multiple ethnicities, which were all or predominantly Caucasians [ 19 , 21 , 22 , 23 , 24 , 27 , 28 , 29 , 31 , 32 , 33 , 39 , 40 , 41 ]. Twelve studies (50%) developed a model with data from phase I, II, or III clinical trials [ 19 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 29 , 31 , 39 , 40 , 41 ], while the remaining studies enrolled subjects from real-world clinical settings [ 18 , 20 , 28 , 30 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ].…”

“…Twenty-two studies (91.7%) described the process of first-order absorption and elimination, while one study employed sequential zero-order and first-order absorption [ 20 ], and another study employed the lag time on absorption [ 19 ]. The plasma concentration of rivaroxaban was measured using high-performance liquid chromatography with tandem mass spectrometry ( n = 19) [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 29 , 30 , 31 , 34 , 35 , 36 , 37 , 39 , 40 , 41 ] or anti-Xa assays ( n = 5) [ 18 , 28 , 32 , 33 , 35 ].…”

Transferability of Published Population Pharmacokinetic Models for Apixaban and Rivaroxaban to Subjects with Obesity Treated for Venous Thromboembolism: A Systematic Review and External Evaluations

“…Since our last literature search, new pharmacokinetic studies have been conducted or are underway. For example, a Pubmed/MEDLINE search in February 2023 using the keywords “rivaroxaban population pharmacokinetics” for 2021–2023 identified five studies [ 45 , 46 , 47 , 48 , 49 ] that would have met our systematic review inclusion criteria by title and abstract. All were single-compartment models with first-order uptake, and none were specifically designed for the obese patient population.…”