Effect of ABCB1 Genotypes on the Pharmacokinetics and Clinical Outcomes of New Oral Anticoagulants: A Systematic Review and Meta-analysis

Abstract

Background: New Oral Anticoagulants (NOACs) are effective and widely used to prevent and treat thromboembolic diseases, but the response to NOACs differs according to ABCB1 genotypes. Objective: We investigated the effects of ABCB1 genotypes on the pharmacokinetics and clinical outcomes of NOACs. Methods: We searched PubMed, Embase, and the Cochrane Library for studies on ABCB1 genotypes published from the inception of these databases until May 23, 2018. The Weighted Mean Difference (WMD) and Odds Ratio (OR) with 95% Confidence Interval (CI) were calculated for continuous and dichotomous data, respectively. Summary results were calculated using a random effects model. Results: Ten studies involving 2609 individuals were included in the systematic review, and three studies involving 535 individuals were included in the meta-analysis. Overall, four ABCB1 single-nucleotide polymorphisms were identified in the review. Carriers of the ABCB1 rs1045642 CC genotype had lower maximum plasma concentration (Cmax) than those of TT (WMD = −16.99 ng/mL; 95% CI = −33.39 to −0.59; P = 0.04), and carriers of the rs2032582 GG genotype showed lower Cmax than those of the A/T allele (WMD = −19.21 ng/mL; 95% CI = −36.62 to −1.80; P = 0.03). Carriers of the rs1045642 CC genotype showed lower area under the curve from time 0 to infinity (AUC0–∞) than those of the T allele (WMD = −78.58 ng·h/mL; 95% CI = −151.14 to −6.01; P = 0.03). ABCB1 rs4148738 genotypes did not affect the risks of ischemic stroke or systemic embolism (OR = 0.88), ischemic events (OR = 0.98), bleeding (OR = 0.94), major bleeding (OR = 1.14), or minor bleeding (OR = 0.94) in patients treated with dabigatran. Conclusion: Cmax was lower in carriers of ABCB1 rs1045642 CC than in those of TT and in carriers of rs2032582 GG than in those of the A/T allele, and AUC0–∞ was lower in carriers of rs1045642 CC than in those of TT. Conversely, ABCB1 rs4148738 genotypes did not affect primary clinical endpoints in dabigatran-administered patients. Future studies should analyze the relationships of ABCB1 genotypes with the pharmacokinetics and clinical outcomes of specific NOACs.

Impact of ABCB1 C3435T Polymorphism on Treatment Response of Vitamin K Antagonists: A Systematic Review and Meta-analysis

“…46) In particular, the effects of ABCB1 C3435T polymorphism on other types of anticoagulants and antiplatelet drugs have been reported. [47][48][49][50] Similar to the results of this study, a meta-analysis that reported a relationship between ABCB1 C3435T polymorphism and treatment response to clopidogrel showed that the ABCB1 3435T allele was associated with a significantly increased incidence rate of bleeding events in the Asian population (OR 1.805, 95% CI 1.124 to 2.900, p=0.015). 49) In addition, the ABCB1 3435T allele was associated with a significantly reduced platelet activity (standardized mean difference with fixed effect model −0.140, 95% CI −0.272 to −0.009, p=0.036).…”

Pharmacogenetics and Precision Medicine Approaches for the Improvement of COVID-19 Therapies

“…Both the FDA and CPIC have recommended to consider both the CYP2C9*2, *3 and VKORC1 (rs9934438) genetic variants for optimizing its safety, that is, bleeding or efficacy in order to achieve precision medicine of warfarin (Dean, 2012;Johnson et al, 2017). Other new oral anticoagulants such as debigatran, rivaroxaban, and apixaban are affected by the ABCB1 genetic variants and should be considered clinically for optimizing the safety and efficacy (Xie et al, 2018;Kanuri and Kreutz, 2019).…”

Using Pharmacogenetics of Direct Oral Anticoagulants to Predict Changes in Their Pharmacokinetics and the Risk of Adverse Drug Reactions

“…The expression of rivaroxaban transporter proteins may be influenced by SNVs of the ABCB1 gene, but information on their clinical significance is inconsistent. The systematic review and meta-analysis by Xie Q. et al (2018) showed that Cmax was lower in carriers of ABCB1 rs1045642 CC than carriers of TT, and carriers of rs2032582 GG than carriers of A/T allele, and AUC0–∞ was lower in rs1045642 CC carriers than in TT carriers [ 48 ]. According to Gouin-Thibault I. et al (2017), ABCB1 polymorphism cannot be considered as a significant determinant of individual variability in pharmacokinetics of rivaroxaban, and combined use of P-gp/CYP3A4 inhibitor clarithromycin with rivaroxaban may require caution in patients at risk of overdose, as it leads to a two-fold increase in AUC genotype ABCB1 [ 26 ].…”