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

Abstract

Low-dose rivaroxaban has been used in Asian patients with direct oral anticoagulants (DOACs) eligible for atrial fibrillation (AF). However, there are few pharmacokinetic (PK) data in Thai patients to support precise dosing. This study aimed to develop a population PK model and determine the optimal rivaroxaban doses in Thai patients. A total of 240 Anti-Xa levels of rivaroxaban from 60 Thai patients were analyzed. A population PK model was established using the nonlinear mixed-effect modeling approach. Monte Carlo simulations were used to predict drug exposures at a steady state for various dosages. Proportions of patients having rivaroxaban exposure within typical exposure ranges were determined. A one-compartment model with first-order absorption best described the data. Creatinine clearance (CrCl) and body weight significantly affected CL/F and V/F, respectively. Regardless of body weight, a higher proportion of patients with CrCl < 50 mL/min receiving the 10-mg once-daily dose had rivaroxaban exposures within the typical exposure ranges. In contrast, a higher proportion of patients with CrCl ≥ 50 mL/min receiving the 15-mg once-daily dose had rivaroxaban exposures within the typical exposure ranges. The study’s findings suggested that low-dose rivaroxaban would be better suited for Thai patients and suggested adjusting the medication’s dose in accordance with renal function.

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.…”