Drug interactions and pharmacogenetic factors contribute to variation in apixaban concentration in atrial fibrillation patients in routine care

Gulilat, Markus; Keller, Denise; Linton, Bradley; Pananos, A. Demetri; Lizotte, Daniel J.; Dresser, George K.; Alfonsi, Jeffrey; Tirona, Rommel G.; Kim, Richard B.; Schwarz, Ute I.

doi:10.1007/s11239-019-01962-2

Cited by 40 publications

(45 citation statements)

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“…Among the other variants investigated in our study, ABCG2 c.421C>A and CES1 c.257+885T>C suggested possible association with bleeding events in apixaban and dabigatran users, respectively, although statistical significance was not reached. Our results on the ABCG2 c.421C>A SNV are in line with the results of earlier prospective studies on plasma concentration and drug clearance 11,15,40 as well as with a case report. 41 Our results on CES1 c.257+885T>C SNV are in line with studies reporting association of the variant with drug plasma concentration.…”

Section: Discussionsupporting

confidence: 92%

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Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users

Lähteenmäki

Vuorinen

Pajula

et al. 2021

Clin Pharma and Therapeutics

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This study aimed to analyze associations between genetic variants and the occurrence of clinical outcomes in dabigatran, apixaban, and rivaroxaban users. This was a retrospective real-world study linking genotype data of three Finnish biobanks with national register data on drug dispensations and healthcare encounters. We investigated several single-nucleotide variants (SNVs) in the ABCG2, ABCB1, CES1, and CYP3A5 genes potentially associated with bleeding or thromboembolic events in direct oral anticoagulant (DOAC) users based on earlier research. We used Cox regression models to compare the incidence of clinical outcomes between carriers and noncarriers of the SNVs or haplotypes. In total, 1,806 patients on apixaban, dabigatran, or rivaroxaban were studied. The ABCB1 c.3435C>T (p.Ile1145=, rs1045642) SNV (hazard ratio (HR) 0.42, 95% confidence interval (CI), 0.18-0.98, P = 0.044) and 1236T-2677T-3435T (rs1128503-rs2032582-rs1045642) haplotype (HR 0.44, 95% CI, 0.20-0.95, P = 0.036) were associated with a reduced risk for thromboembolic outcomes, and the 1236C-2677G-3435C (HR 2.55, 95% CI, 1.03-6.36, P = 0.044) and 1236T-2677G-3435C (HR 5.88, 95% CI, 2.35-14.72, P < 0.001) haplotypes with an increased risk for thromboembolic outcomes in rivaroxaban users. The ABCB1 c.2482-2236G>A (rs4148738) SNV associated with a lower risk for bleeding events (HR 0.37, 95% CI, 0.16-0.89, P = 0.025) in apixaban users. ABCB1 variants are potential factors affecting thromboembolic events in rivaroxaban users and bleeding events in apixaban users. Studies with larger numbers of patients are warranted for comprehensive assessment of the pharmacogenetic associations of DOACs and their relevance for clinical practice.Direct oral anticoagulants (DOACs) are increasingly used in the context of various clinical conditions and procedures, including atrial fibrillation (ischemic stroke prevention), deep vein thrombosis, and pulmonary embolism. DOACs have favorable pharmacodynamic and pharmacokinetic properties and do not require continuous therapeutic monitoring except in specific

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Section: Discussionsupporting

confidence: 92%

“…The effect of genetic factors on the pharmacokinetics of DOACs have been investigated in several studies 7–9 . Indications of association between genotypes and drug plasma levels have been found in some studies, 10–17 but also contradictory findings have been reported 5,18,19 …”

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confidence: 99%

Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users

Lähteenmäki

Vuorinen

Pajula

et al. 2021

Clin Pharma and Therapeutics

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“…While the time‐point of TL is well defined, the peak period is within a range of 1.5‐4 hours (eg, apixaban) 19 . The individual pharmacokinetics (ADME) differs in each patient (eg, nutrition, age, heparin/renal function, co‐medication and genetic polymorphisms), 20 which renders PL highly variable and impedes clinical outcome correlations. The CV of PL in our study was between 31% and 54% for factor Xa inhibitors and 70% for dabigatran in accordance with the literature 21,22 .…”

Section: Discussionmentioning

confidence: 99%

Plasma levels do not predict thrombin generation in patients taking direct oral anticoagulants

Metze

Klöter

Stöbe

et al. 2021

Int J Lab Hematology

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Background The antithrombotic effect of direct oral anticoagulants (DOAC) in specific clinical scenarios is difficult to assess. Objective This study aimed to evaluate the effect of DOAC on thrombin generation (TG) in relation to their plasma level. Methods Eighty patients newly started on anticoagulation were included, 20 patients for each DOAC—apixaban, edoxaban, rivaroxaban, and dabigatran. Plasma was sampled before DOAC (baseline), at plasma peak time, 6 and 12 hours after starting DOAC for quantification of drug levels and TG. Results The baseline TG before DOAC intake showed inter‐individual variability. All DOACs significantly prolonged lag time (LT) and time to peak (TTP), but did not change endogenous thrombin potential (ETP). Anti‐Xa inhibitors but not dabigatran reduced thrombin peak, but the effect of apixaban at plasma peak was less pronounced (factor 1.6). LT and TTP prolongation of dabigatran was lower compared to anti‐Xa inhibitors. All DOACs showed a nonlinear dose‐response relationship, with the greatest antithrombotic effect at lower DOAC plasma levels. The inhibition of TG parameters between baseline and peak was parallel between individual patients but the coefficient of variation of TG was lower compared to drug levels. Conclusion The antithrombotic effect at DOAC peak plasma level measured by TG depends on the patient‐specific baseline TG level and the drug‐specific inhibition by the particular DOAC. Although peak plasma levels have a high variability, the variation of TG is lower compared to drug levels. Therefore, TG assays may be superior to plasma levels in the assessment of the intensity of anticoagulation.

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“…У пациентки было обнаружено 4 полиморфизма, которые могут быть ответственны за изменение фармакокинетики препарата: гомозиготные формы по мутантному аллелю ABCB1 rs2032582, rs1045642, а также CYP3A5 rs776746, в т. ч. гетерозигота по ABCG2 rs2231142 [21]. В исследовании 2020 г. на выборке 358 человек с фибрилляцией предсердий авторы продемонстрировали ассоциацию между ABCG2 421 C > A и повышенными пиковыми и минимальными концентрациями апиксабана в плазме крови [22]. Однако в исследовании A.V.…”

Section: Discussionunclassified

Effect of polymorphisms in CYP3A422 (rs35599367) C>T, CYP3A53 (rs776746) A>G, ABCB1 (rs4148738) C>T and ABCB1 (rs1045642) C>T genes on apixaban anticoagulation: pilot study results

et al. 2021

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Introduction. Apixaban is a direct oral anticoagulant prescribed for treatment and prevention of venous thromboembolism (VTE) and for prevention of stroke in patients with nonvalvular atrial fibrillation. Direct oral anticoagulants (DOACs) such as apixaban are rapidly replacing warfarin therapy due to improved efficacy and safety profile shown in clinical trials. However, anticoagulants can cause serious and adverse drug reactions (ADRs).Aim. Study of the effect of carriage of polymorphisms in CYP3A4*22 (rs35599367) C>T, CYP3A5*3 (rs776746) A>G, ABCB1 (rs4148738) C>T and ABCB1 (rs1045642) C>T genes on the change in prothrombin time (PT) and activated partial thromboplastin time (aPTT) in patients using apixaban.Materials and methods. A total of 36 patients were enrolled onto this prospective observational study. All patients received apixaban at doses in accordance with instructions on how to administer the drug. Atrial fibrillation was diagnosed in 26 patients, and secondary thrombotic complications in 23 patients. To perform pharmacogenetic tests and measure aPTT and PT parameters, venous blood samples from each patient were drawn on Days 4-5 after prescription of apixaban. The PharmGKB database was used to select candidate genes for the study. Genotyping was performed using the real-time polymerase chain reaction technique. Statistical analysis: data were analyzed by using IBM SPSS Statistics program, Version 23.0.Results. In our study, we assessed the effect of polymorphisms in ABCB1 (rs1045738) C>T, ABCB1 (rs4148642) C>T genes on the aPTT and PT parameters. No statistically significant associations were found.Conclusion. The differences between PT and APTT values in patients using apixaban in the groups with different polymorphisms in ABCB1 (rs1045738) C>T, ABCB1 (rs4148642) C>T gene were not statistically significant. Further studies are necessary to assess the effect of pharmacogenetics on the safety and efficacy profile of apixaban.

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Drug interactions and pharmacogenetic factors contribute to variation in apixaban concentration in atrial fibrillation patients in routine care

Cited by 40 publications

References 56 publications

Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users

Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users

Plasma levels do not predict thrombin generation in patients taking direct oral anticoagulants

Effect of polymorphisms in CYP3A422 (rs35599367) C>T, CYP3A53 (rs776746) A>G, ABCB1 (rs4148738) C>T and ABCB1 (rs1045642) C>T genes on apixaban anticoagulation: pilot study results

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Drug interactions and pharmacogenetic factors contribute to variation in apixaban concentration in atrial fibrillation patients in routine care

Cited by 40 publications

References 56 publications

Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users

Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users

Plasma levels do not predict thrombin generation in patients taking direct oral anticoagulants

Effect of polymorphisms in CYP3A4*22 (rs35599367) C>T, CYP3A5*3 (rs776746) A>G, ABCB1 (rs4148738) C>T and ABCB1 (rs1045642) C>T genes on apixaban anticoagulation: pilot study results

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Effect of polymorphisms in CYP3A422 (rs35599367) C>T, CYP3A53 (rs776746) A>G, ABCB1 (rs4148738) C>T and ABCB1 (rs1045642) C>T genes on apixaban anticoagulation: pilot study results