Jurij Zdovc(1), Maja Petre(1,2), Iztok Grabnar(1), Mitja Pišlar(1), Uroš Potocnik(3), Aleš Mrhar(1)
(1) – Univerza v Ljubljani, Faculty of Pharmacy; (2) – Univerzitetni Klinicni Center Maribor; (3) – Univerza v Mariboru, Faculty of Medicine
Objectives: Rivaroxaban is a relatively recent, oral, direct Factor Xa inhibitor. In patients undergoing hip or knee replacement surgery it is indicated for prevention of deep vein thrombosis which may lead to pulmonary embolism [1]. After administration, approximately two thirds of the dose are metabolized in liver, from which one half is then excreted via kidneys and the other half via hepatobiliary route. One third of the administered dose is excreted unchanged via kidneys, most of it through renal secretion [2]. The in-vitro and in-vivo studies demonstrate that the transporters involved in the process of renal secretion are the protein ABCB1, also known as P-glycoprotein (P-gp) and the Breast cancer resistance protein. As a consequence, rivaroxaban is advised not to be taken concomitantly with strong P-gp inducers or inhibitors [3–5]. Our study aims to assess the population PK and PD of rivaroxaban in patients undergoing the total hip or knee replacement. We aim to evaluate the influence of the ABCB1 gene expression and two single nucleotide polymorphisms (SNP) on the PK and PD of rivaroxaban.
Methods: There were 17 patients included in the study and all of them were scheduled for their first total hip or knee replacement. Before the surgery we performed the polymorphism genotyping and the ABCB1 gene expression assay. 6 h after the surgery the patients started with the thromboprophylactic therapy, which consisted of 10 mg of rivaroxaban per 24h, on an empty stomach. Subsequently we measured the concentration of rivaroxaban in plasma and performed the tests of coagulation. A total of 82 plasma concentration-time points were used to develop the PK model. Some of the measurements were below the limit of quantification (BQL, < 1 ng/mL), so we used the M3 estimation method, together with the Laplacian estimation. A one-compartment model with first-order absorption was fitted to the logarithmically transformed plasma concentrations. The first order conditional estimation with interaction was used as an estimation method for the parameters. We tested the influence of the following covariates: age, sex, genetic polymorphisms on the gene ABCB1 – rs10445642 and rs4148738, body mass index, smoking, glomerular filtration, concomitant medication and the ABCB1 expression.
Results: A simple one-compartment PK model with first order absorption best fitted our data. Due to the difficulties in the convergence we transformed the data to the logarithmic scale. The ka was estimated at 0.147 h-1(with a relative standard error of 14.3 %), the oral Cl for the person with the gene expression of 1.25 was 6.12 L/h (15.8 %) and the volume of distribution was estimated to 96.8 L (13.1 %). The typical value of the parameter relating the gene expression and Cl was 0.817 (28.8 %). We were able to estimate the inter-individual variability on ka and Cl, which were 204 % (8.63 %) and 70.9 % (13.6 %), respectively. The residual variability was proportional and estimated at 59.6 % (12.7 %). During the covariate modeling the expression of ABCB1 gene entered the final model and the final equation for Cl was Cl = 6.12*(ABCB1/1.25)0.817. From this relation we observed that the Cl of rivaroxaban decreases with a lower ABCB1 gene expression, which corresponds with the fact that rivaroxaban is the substrate for the P-gp. In almost all subjects (16 out of 17) the gene expression decreased after the surgery and the Cl lowered accordingly. With respect to the PD, prothrombin time (PT) and partial thromboplastin time (aPTT) were both linearly associated to the natural logarithm of the rivaroxaban concentrations in plasma. The intercept PT and aPTT were estimated to the 12.8 s (4.48 %) and 32.9 s (4.08 %), respectively. The residual error was modeled with additive type of error and proportional type of error in the PT and aPTT models, respectively.
Conclusions: The study showed that the one-compartment PK model with the first order absorption is a suitable model to describe the PK of rivaroxaban. We confirmed the correlation between the ABCB1 gene expression and the Cl of rivaroxaban, which corresponds to the fact that the rivaroxaban is a P-gp substrate. The analysis also indicated that the PT and aPTT increase with the increased dose of rivaroxaban and are good indicators of PD. An interesting finding was also that the ABCB1 gene expression decreased after the orthopedic surgery. We were not able to explain that phenomenon and further research is needed to assess and explain the mechanism.
References:
[1] Janssen Pharmaceuticals (2016) Xarelto.
[2] Weinz C, Schwarz T, Kubitza D, et al (2009) Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and jumans. Drug Metab Dispos 37:1056–1064 . doi: 10.1124/dmd.108.025569.shown
[3] Gnoth MJ, Buetehorn U, Muenster U, et al (2011) In vitro and in vivo P-glycoprotein transport characteristics of rivaroxaban. J Pharmacol Exp Ther 338:372–380 . doi: 10.1124/jpet.111.180240
[4] Mueck W, Kubitza D, Becka M (2013) Co-administration of rivaroxaban with drugs that share its elimination pathways: Pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol 76:455–466 . doi: 10.1111/bcp.12075
[5] Gong IY, Mansell SE, Kim RB (2013) Absence of both MDR1 (ABCB1) and Breast Cancer Resistance Protein (ABCG2) Transporters Significantly Alters Rivaroxaban Disposition and Central Nervous System Entry. Basic Clin Pharmacol Toxicol 112:164–170 . doi: 10.1111/bcpt.12005
Reference: PAGE 27 (2018) Abstr 8738 [www.page-meeting.org/?abstract=8738]
Poster: Drug/Disease Modelling - Other Topics