Tayebeh EsmaeiliI(1), Saeed Rezaee(1), Mahm0ood Rezaee(2), Azadeh Davoudian(2)
(1)Pharmaceutics Department, Faculty of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran, ( 2)Cardiology Department, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
Backgrounds: Recently, rivaroxaban has been used for the approved indications in Iranian patients and has been developed as a favored alternative to coumarin derivatives. Predictable pharmacokinetics and pharmacodynamics allow rivaroxaban fixed dosing regimens without routine coagulation monitoring [1] but there is still the necessity to monitor and predict the effects of this drug in specific conditions and different populations [2]. However, pharmacokinetics and pharmacodynamics of this drug have not been studied in the Iranian population. On the other hand, there are some published and unpublished reports about the unpredictable effects of this drug among different populations and in Iranian patients [3-5]. The main goal of the current study was to determine the rivaroxaban population pharmacokinetic parameters in the Iranian population.
Methods: Sixty-nine Iranian patients over the age of 18, who received rivaroxaban (mostly for the treatment of NVAF) participated in this study from February 2019 to May 2019. Rivaroxaban doses were 10, 15, or 20 mg, once or twice a day for at least seven days to ensure achieving pharmacokinetic steady-state condition. Patients with internal bleeding, cirrhosis, incidence or history of stroke or transient ischemic attack, and concurrent treatment with other anticoagulants were excluded from the study. A sparse sampling method was used in this study. Plasma concentrations of rivaroxaban were measured using a fully validated high-performance liquid chromatography/tandem mass spectrometry (HPLC/ MS-MS) method[6]. The lower limit of quantitation was 3 ng/mL, and the calibration curve was linear up to 1600 ng/ml. A total of 126 plasma concentration points versus time were used to set up the PK model. COSSAC (Conditional Sampling use for Stepwise Approach based on Correlation tests) algorithm of Monolix software was used for covariate model building[7]. The tested patients’ covariates were rivaroxaban dose, the indication of rivaroxaban administration, age, sex, height, body weight, body mass index, body fat, lean body mass, body surface area, BUN, albumin serum, total bilirubin, Child-Turcotte-Pugh (CTP) score and Creatinine clearance (Clcr). The best covariate models were chosen according to the smallest value for corrected Bayesian information criteria (BICc)[8]. Data were analyzed using MONOLIX software with the stochastic approximation of the standard expectation-maximization (SAEM) algorithm for nonlinear mixed-effects models without approximations.
Results: Sixty-one patients with NVAF and eight patients with other approved indications of rivaroxaban, including PE and DVT were involved in this study. The median age of patients was 64 years (range from 36 to 86 years) and 33 patients were men. One hundred and twenty-six rivaroxaban concentrations (between 7 and 898 ng/ml) were used to build the pharmacokinetic model. A one-compartment model with first-order absorption and elimination fitted the data well. The proportional error model best described the residual variability of the PK models. The population estimates of the base PK model for oral volume of distribution (V/F) and clearance (CL/F) was 54.5 L and 3.7 L/h, respectively. The first-order absorption rate constant (Ka) was fixed at 0.821 that was reported previously[9]. Transformed Clcr based on MDRD equation for Cl/F and CTP Score for Cl/F were selected as covariates in the full population pharmacokinetic model. In the final population pharmacokinetic model, the inclusion of the mentioned covariates decreased the inter-individual variability of CL/F from 75.2% to 61.3%. A negative correlation was observed between the CTP score and CL of rivaroxaban whereas a positive correlation was observed between the Clcr and Cl of rivaroxaban. A negative correlation was observed between the CTP score and CL of rivaroxaban whereas a positive correlation was observed between the Clcr and rivaroxaban clearance.
Conclusion: In Iranian patients, the pharmacokinetic profile of rivaroxaban is influenced by the liver and renal function simultaneously and it is necessary to check liver and kidney functions in patients who go under treatment with rivaroxaban different dosing schedules.
References:
[1] Girgis IG, Patel MR, Peters GR, Moore KT, Mahaffey KW, Nessel CC et al. Population Pharmacokinetics and Pharmacodynamics of Rivaroxaban in Patients with Non-valvular Atrial Fibrillation: Results from ROCKET AF. The Journal of Clinical Pharmacology. 2014;54(8):917-27. doi:10.1002/jcph.288.
[2] Friedman RJ. NewOral Anticoagulants for Thromboprophylaxis after Elective Total Hip and Knee Arthroplasty. Thrombosis Journal. 2010;2010. doi:10.1155/2010/280731.
[3] Mueck W, Stampfuss J, Kubitza D, Becka M. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet. 2014;53(1):1-16. doi:10.1007/s40262-013-0100-7.
[4] Miklic M, Mavri A, Vene N, Söderblom L, Božic-Mijovski M, Pohanka A et al. Intra-and inter-individual rivaroxaban concentrations and potential bleeding risk in patients with atrial fibrillation. European journal of clinical pharmacology. 2019;75(8):1069-75.
[5] Rahimizadeh A, Malekmohammadi Z, Williamson WL, Rahimizadeh S, Amirzadeh M, Asgari N. Rivaroxaban-induced acute cervical spine epidural hematoma: Report of a case and review. Surgical Neurology International. 2019;10.
[6] Derogis PBM, Sanches LR, de Aranda VF, Colombini MP, Mangueira CLP, Katz M et al. Determination of rivaroxaban in patient’s plasma samples by anti-Xa chromogenic test associated to High Performance Liquid Chromatography tandem Mass Spectrometry (HPLC-MS/MS). PloS one. 2017;12(2):e0171272.
[7] Monolix version 2019R2. Antony, France: Lixoft SAS. 2020. http://lixoft.com/produ cts/monolix/. Accessed 14 Nov 2020.
[8] Kadane JB, Lazar NA. Methods and criteria for model selection. Journal of the American statistical Association. 2004;99(465):279-90.
[9] Willmann S, Zhang L, Frede M, Kubitza D, Mueck W, Schmidt S et al. Integrated Population Pharmacokinetic Analysis of Rivaroxaban Across Multiple Patient Populations. CPT Pharmacometrics Syst Pharmacol. 2018;7:309-20. doi:10.1002/psp4.12288.
Reference: PAGE 29 (2021) Abstr 9758 [www.page-meeting.org/?abstract=9758]
Poster: Drug/Disease Modelling - Other Topics