Downregulation of ABCB1 gene in patients with total hip or knee arthroplasty influences pharmacokinetics of rivaroxaban: a population pharmacokinetic-pharmacodynamic study
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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.
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.
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.
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.
KeywordsRivaroxaban Population pharmacokinetics/pharmacodynamics ABCB1 expression Orthopedic surgery
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.
This work was financially supported by the Slovenian Research Agency (ARRS Grants P1-0189 and P3-0067).
Compliance with ethical standards
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.
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