Abstract
Purpose
Rivaroxaban is a substrate for ABCB1 transporter and is commonly used in patients undergoing hip or knee replacement surgery for thromboprophylaxis. The objective of this study was to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model to investigate the influence of ABCB1 gene expression and polymorphism on rivaroxaban exposure and anticoagulation effects.
Methods
Five blood samples per patient were collected during 5 days after the surgery for the determination of rivaroxaban concentration in plasma and for determination of prothrombin time and partial thromboplastin time. Non-linear mixed effects model was used for a population PK-PD analysis and for testing covariate effects.
Results
A one-compartment PK model with first-order absorption adequately described the pharmacokinetic data. The typical oral clearance (CL/F) was 6.12 L/h (relative standard error, 15.8%) and was associated with ABCB1 expression. Compared to base line before the surgery, a significant ABCB1 downregulation was observed 5 days after the surgery (p < 0.001). Prothrombin time and partial thromboplastin time were both linearly associated to the logarithm of the rivaroxaban plasma concentration.
Conclusions
We confirmed that variable rivaroxaban CL/F is associated with ABCB1 expression, which is in accordance with previous studies on P-glycoprotein involvement in rivaroxaban PK. Furthermore, we observed the downregulation of ABCB1 expression after the surgery. The cause remains unclear and further research is needed to explain the underlying mechanisms.
Similar content being viewed by others
References
Agnelli G (2004) Prevention of venous thromboembolism in surgical patients. Circulation 110:4–13. https://doi.org/10.1161/01.CIR.0000150639.98514.6c
Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW (2008) Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 133:381S–453S. https://doi.org/10.1378/chest.08-0656
Gillespie W, Murray D, Gregg PJ, Warwick D (2000) Risks and benefits of prophylaxis against venous thromboembolism in orthopaedic surgery. J Bone Joint Surg Br 82:475–479. https://doi.org/10.1302/0301-620X.82B4.10452
Mueck W, Eriksson BI, Bauer KA, Borris L, Dahl OE, Fisher WD, Gent M, Haas S, Huisman MV, Kakkar AK, Kälebo P, Kwong LM, Misselwitz F, Turpie AGG (2008) Population pharmacokinetics and pharmacodynamics of rivaroxaban--an oral, direct factor Xa inhibitor--in patients undergoing major orthopaedic surgery. Clin Pharmacokinet 47:203–216. https://doi.org/10.2165/00003088-200847030-00006
Duggan ST (2012) Rivaroxaban: a review of its use for the prophylaxis of venous thromboembolism after total hip or knee replacement surgery. Am J Cardiovasc Drugs 12:57–72. https://doi.org/10.2165/11208470-000000000-00000
Antoniou S (2015) Rivaroxaban for the treatment and prevention of thromboembolic disease. J Pharm Pharmacol 67:1119–1132. https://doi.org/10.1111/jphp.12387
Frostick S (2016) Pharmacological thromboprophylaxis and total hip or knee replacement. Br J Nurs 25:45–53. https://doi.org/10.12968/bjon.2016.25.1.45
Friedman RJ (2010) New oral anticoagulants for thromboprophylaxis after elective total hip and knee arthroplasty. Thrombosis 2010:280731. https://doi.org/10.1155/2010/280731
Stampfuss J, Kubitza D, Becka M, Mueck W (2013) The effect of food on the absorption and pharmacokinetics of rivaroxaban. Int J Clin Pharmacol Ther 51:549–561. https://doi.org/10.5414/CP201812
(2016) Janssen Pharmaceuticals Xarelto
Kubitza D, Becka M, Voith B et al (2005) Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 78:412–421. https://doi.org/10.1016/j.clpt.2005.06.011
Mueck W, Stampfuss J, Kubitza D, Becka M (2014) Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet 53:1–16. https://doi.org/10.1007/s40262-013-0100-7
Weinz C, Schwarz T, Kubitza D, Mueck W, Lang D (2009) Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab Dispos 37:1056–1064. https://doi.org/10.1124/dmd.108.025569.shown
Gnoth MJ, Buetehorn U, Muenster U, Schwarz T, Sandmann S (2011) In vitro and in vivo P-glycoprotein transport characteristics of rivaroxaban. J Pharmacol Exp Ther 338:372–380. https://doi.org/10.1124/jpet.111.180240
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. https://doi.org/10.1111/bcp.12075
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. https://doi.org/10.1111/bcpt.12005
Hodges LM, Markova SM, Chinn LW, Gow JM, Kroetz DL, Klein TE, Altman RB (2011) Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics 21:152–161. https://doi.org/10.1097/FPC.0b013e3283385a1c.
Hodin S, Basset T, Jacqueroux E, Delezay O (2017) In vitro comparison of the role of P-glycoprotein and breast cancer resistance protein on direct oral anticoagulants disposition. Eur J Drug Metab Pharmacokinet 43:183–191. https://doi.org/10.1007/s13318-017-0434-x
Lorenzini KI, Daali Y, Fontana P et al (2016) Rivaroxaban-induced hemorrhage associated with ABCB1 genetic defect. Front Pharmacol 7:1–5. https://doi.org/10.3389/fphar.2016.00494
Gouin-Thibault I, Delavenne X, Blanchard A, Siguret V, Salem JE, Narjoz C, Gaussem P, Beaune P, Funck-Brentano C, Azizi M, Mismetti P, Loriot MA (2017) Interindividual variability in dabigatran and rivaroxaban exposure: contribution of ABCB1 genetic polymorphisms and interaction with clarithromycin. J Thromb Haemost 15:273–283. https://doi.org/10.1111/jth.13577
Sennesael A, Panin N, Vancraeynest C et al (2018) Effect of ABCB1 genetic polymorphisms on the transport of rivaroxaban in HEK293 recombinant cell lines. Sci Rep 8:6–11. https://doi.org/10.1038/s41598-018-28622-4
Sennesael A, Larock A, Douxfils J et al (2018) Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study. Thromb J 16:1–8. https://doi.org/10.1186/s12959-018-0183-3
Mueck W, Becka M, Kubitza D, Voith B, Zuehlsdorf M (2007) Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban - an oral, direct factor Xa - inhibitor in healthy subjects. Int J Clin Pharmacol Ther 45:335–344. https://doi.org/10.5414/CPP45335
Mueck W, Borris LC, Dahl OE et al (2008) Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost 100:453–461. https://doi.org/10.1160/07-12-0714
Mueck W, Lensing AWA, Agnelli G, Decousus H, Prandoni P, Misselwitz F (2011) Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 50:675–686. https://doi.org/10.2165/11595320-000000000-00000
Girgis IG, Patel MR, Peters GR, et al (2014) Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: results from ROCKET AF. https://doi.org/10.1002/jcph.288
Xu XS, Moore K, Burton P, Stuyckens K, Mueck W, Rossenu S, Plotnikov A, Gibson M, Vermeulen A (2012) Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes. Br J Clin Pharmacol 74:86–97. https://doi.org/10.1111/j.1365-2125.2012.04181.x
Willmann S, Zhang L, Frede M, Kubitza D, Mueck W, Schmidt S, Solms A, Yan X, Garmann D (2018) Integrated population pharmacokinetic analysis of rivaroxaban across multiple patient populations. CPT Pharmacometrics Syst Pharmacol 7:309–320. https://doi.org/10.1002/psp4.12288
Levey A, Green T, Kusek J, Beck G (2000) MDRD Study Group. A simplified equation to predict glomerular filtration rate from serum creatinine (abstract). J Am Soc Nephrol 11:155A (A0828)
Douxfils J, Tamigniau A, Chatelain B, Chatelain C, Wallemacq P, Dogné JM, Mullier F (2013) Comparison of calibrated chromogenic anti-Xa assay and PT tests with LC-MS/MS for the therapeutic monitoring of patients treated with rivaroxaban. Thromb Haemost 110:723–731. https://doi.org/10.1160/TH13-04-0274
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262
Sudchada P, Oo-Puthinan S, Kerdpin O, Saelim N (2010) ABCB1 gene expression in peripheral blood mononuclear cells in healthy Thai males and females. Genet Mol Res 9:1177–1185. https://doi.org/10.4238/vol9-2gmr813
Beal S, Sheiner LB, Boeckmann A, Bauer RJ (2009) NONMEM user’s guides. (1989–2009). Ellicott City, MD, USA
Bergstrand M, Karlsson MO (2009) Handling data below the limit of quantification in mixed effect models. AAPS J 11:371–380. https://doi.org/10.1208/s12248-009-9112-5
Hegarty JP, Sangster W, Harris LR, Stewart DB (2014) Proton pump inhibitors induce changes in colonocyte gene expression that may affect Clostridium difficile infection. Surgery 156:972–978. https://doi.org/10.1016/j.surg.2014.06.074
Rekersbrink CPS, Klotz U, Fromm MF (2001) Interaction of omeprazole , lansoprazole and pantoprazole with P-glycoprotein. 551–557. https://doi.org/10.1007/s00210-001-0489-7
Paré G, Eriksson N, Lehr T, Connolly S, Eikelboom J, Ezekowitz MD, Axelsson T, Haertter S, Oldgren J, Reilly P, Siegbahn A, Syvanen AC, Wadelius C, Wadelius M, Zimdahl-Gelling H, Yusuf S, Wallentin L (2013) Genetic determinants of dabigatran plasma levels and their relation to bleeding. Circulation 127:1404–1412. https://doi.org/10.1161/CIRCULATIONAHA.112.001233
Kryukov AV, Sychev DA, Andreev DA, Ryzhikova KA, Grishina EA, Ryabova AV, Loskutnikov MA, Smirnov VV, Konova OD, Matsneva IA, Bochkov PO (2018) Influence of ABCB1 and CYP3A5 gene polymorphisms on pharmacokinetics of apixaban in patients with atrial fibrillation and acute stroke. Pharmgenomics Pers Med 11:43–49. https://doi.org/10.2147/PGPM.S157111
Ueshima S, Hira D, Fujii R, Kimura Y, Tomitsuka C, Yamane T, Tabuchi Y, Ozawa T, Itoh H, Horie M, Terada T, Katsura T (2017) Impact of ABCB1, ABCG2, and CYP3A5 polymorphisms on plasma trough concentrations of apixaban in Japanese patients with atrial fibrillation. Pharmacogenet Genomics 27:329–336. https://doi.org/10.1097/FPC.0000000000000294
Eikelboom JW, Quinlan DJ, Hirsh J, et al (2017) Laboratory monitoring of non–vitamin K antagonist oral anticoagulant use in patients with atrial fibrillation: a review. 1–9 . doi: https://doi.org/10.1001/jamacardio.2017.0364
Freyburger G, Macouillard G, Labrouche S, Sztark F (2011) Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: two observational studies in patients undergoing total hip or total knee replacement. Thromb Res 127:457–465. https://doi.org/10.1016/j.thromres.2011.01.001
Funding
This work was financially supported by the Slovenian Research Agency (ARRS Grants P1-0189 and P3-0067).
Author information
Authors and Affiliations
Contributions
MPe, AM, MV, UP, and IG conceived and designed the study. MV recruited the patients and was the principal clinical investigator. MPe, KR, and UP performed the biochemical and genetic analyses. JZ, MPi, and IG analyzed the data. JZ and IG drafted the first manuscript. UP and AM provided scientific supervision. All authors reviewed and approved the final manuscript.
Corresponding author
Ethics declarations
The study was conducted in accordance with the Helsinki declaration and was approved by the National Medical Ethics Committee of the Republic of Slovenia (168/07/11). Written informed consent was obtained from all patients prior to inclusion in the study.
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
(DOCX 2944 kb)
Rights and permissions
About this article
Cite this article
Zdovc, J., Petre, M., Pišlar, M. et al. Downregulation of ABCB1 gene in patients with total hip or knee arthroplasty influences pharmacokinetics of rivaroxaban: a population pharmacokinetic-pharmacodynamic study. Eur J Clin Pharmacol 75, 817–824 (2019). https://doi.org/10.1007/s00228-019-02639-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00228-019-02639-8