Rivaroxaban population pharmacokinetic and pharmacodynamic modeling in Iranian patients

Abstract

What is Known and Objective Although predictable pharmacokinetic and pharmacodynamic of rivaroxaban allow fixed dosing regimens without routine coagulation monitoring, there is still the necessity to monitor and predict the effects of rivaroxaban in specific conditions and different populations. The current study was designed and conducted to analyze the rivaroxaban population pharmacokinetics in Iranian patients and establish a pharmacokinetic/pharmacodynamic model to predict the relationship between rivaroxaban concentration and its anticoagulant activity. Methods A sequential nonlinear mixed effect pharmacokinetic/pharmacodynamic modeling method was used to establish the relation between rivaroxaban concentration and anti‐factor Xa activity, prothrombin time, and activated partial thromboplastin time (aPTT) as pharmacodynamic biomarkers in a population of sixty‐nine Iranian patients under treatment with oral rivaroxaban. Rivaroxaban plasma concentration was quantified by a validated high‐performance liquid chromatography‐tandem mass spectrometry. Results and Discussion The typical population values (inter‐individual variability%) of the oral volume of distribution and clearance for a one‐compartment model were 61.2 L (21%) and 3.68 L·h−1 (61%), respectively. Creatinine clearance and Child‐Turcotte‐Pugh score were found to affect the clearance. A direct link linear structural model best fitted the data for both prothrombin time and aPTT. The baseline estimates of aPTT and prothrombin time in the population were 35.0 (15%) and 12.6 (2%) seconds, respectively. The slope of the relationship between apTT, prothrombin time, and rivaroxaban concentration was 0.033 (28%) and 0.018 (54%) s·ml·ng−1, respectively. The selected model for anti‐factor Xa activity consisted of a direct link inhibitory Emax model with Hill coefficient. The maximum level of inhibition (Emax) was 4 IU·ml−1. The concentration of rivaroxaban producing 50% of the maximum inhibitory effect (EC50) was 180 (24%) ng·ml−1, and Hill coefficient (γ) was 1.44 (108%). No covariates showed a statistically significant effect on PT and activated partial thromboplastin time prolonging properties and anti‐factor Xa activity. What is New and Conclusion Our results confirmed that pharmacokinetic/pharmacodynamic models similar to those of the other studies describe the relationship between the rivaroxaban concentration and its anticoagulant effect in Iranian patients. However, considerable differences were observed in the parameters of the pharmacodynamics–pharmacokinetic models with the results of other reports that can explain the unpredictable effects of rivaroxaban in some patients.

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

“…In the covariate analysis, the final model revealed that CL/F and V/F of rivaroxaban increase by increasing CrCl and body weight, respectively. Several previous studies showed the significant effect of CrCl on rivaroxaban CL/F [20,24,34,[39][40][41][42], thus, our finding confirmed this relationship. Because rivaroxaban is partly excreted through the kidneys, reduced renal function results in lower drug clearance [19].…”

“…Second, the number of patients concomitantly receiving inducers and inhibitors of CYP3A4 and/or P-glycoprotein was small, so the effect of the drug-drug interactions [19,20,48] could not be evaluated. Third, we did not explore other covariates (i.e., genetic polymorphisms, hepatic impairment) which can cause PK variability of rivaroxaban [34,42,49,50]. A previous study revealed that mild hepatic impairment decreased drug clearance and increased drug exposure, resulting in a prolonged prothrombin time [50].…”

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 ,…”

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.…”