Oral Anticoagulant Therapy

Ageno, Walter; Gallus, Alexander; Wittkowsky, Ann K.; Crowther, Mark; Hylek, Elaine M.; Palareti, Gualtiero

doi:10.1378/chest.11-2292

Cited by 1,307 publications

(641 citation statements)

References 378 publications

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“…Genetic factors affect patients’ responses to warfarin and are important considerations when calculating appropriate dosages as certain genotypes are associated with increased bleeding complications 11. Polymorphisms within the CYP2C9 gene influence the activity of this isoenzyme, whereby individuals who are homozygous for the wild‐type CYP2C9*1 allele have an extensive metabolizer predicted phenotype, whereas individuals who possess 1 or 2 copies of the CYP2C9*2 or CYP2C9*3 variant alleles are intermediate metabolizers and require lower doses of warfarin than extensive metabolizers 11.…”

Section: Discussionmentioning

confidence: 99%

“…Warfarin is a widely used anticoagulant medication that is administered as a racemic mixture of S‐ and R‐enantiomers 11. S‐Warfarin, which is responsible for most of the pharmacological activity of warfarin, is metabolized primarily by CYP2C9; the R‐enantiomer, which is 2.7 to 3.8 times less potent than S‐warfarin, is metabolized by CYP1A2 and CYP3A4 11.…”

mentioning

confidence: 99%

“…S‐Warfarin, which is responsible for most of the pharmacological activity of warfarin, is metabolized primarily by CYP2C9; the R‐enantiomer, which is 2.7 to 3.8 times less potent than S‐warfarin, is metabolized by CYP1A2 and CYP3A4 11. Because it is likely that patients receiving isavuconazole therapy may also require treatment with warfarin or with other substrates of CYP2C9 or CYP1A2, a phase 1 trial was conducted to evaluate the potential pharmacokinetic (PK) and pharmacodynamic (PD) interaction between therapeutic doses of isavuconazole and warfarin in healthy adults.…”

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confidence: 99%

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Pharmacokinetic and Pharmacodynamic Evaluation of the Drug‐Drug Interaction Between Isavuconazole and Warfarin in Healthy Subjects

Desai

Yamazaki

Dietz

et al. 2016

Clinical Pharm in Drug Dev

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This phase 1 trial evaluated pharmacokinetic and pharmacodynamic interactions between the novel triazole antifungal agent isavuconazole and warfarin in healthy adults. Multiple doses of isavuconazole were administered as the oral prodrug, isavuconazonium sulfate (372 mg 3 times a day for 2 days loading dose, then 372 mg once daily thereafter; equivalent to isavuconazole 200 mg), in the presence and absence of single doses of oral warfarin sodium 20 mg. Coadministration with isavuconazole increased the mean area under the plasma concentration‐time curves from time 0 to infinity of S‐ and R‐warfarin by 11% and 20%, respectively, but decreased the mean maximum plasma concentrations of S‐ and R‐warfarin by 12% and 7%, respectively, relative to warfarin alone. Mean area under the international normalized ratio curve and maximum international normalized ratio were 4% lower in the presence vs absence of isavuconazole. Mean warfarin area under the prothrombin time curve and maximum prothrombin time were 3% lower in the presence vs absence of isavuconazole. There were no serious treatment‐emergent adverse events (TEAEs), and no subjects discontinued the study due to TEAEs. All TEAEs were mild in intensity. These findings indicate that coadministration with isavuconazole has no clinically relevant effects on warfarin pharmacokinetics or pharmacodynamics.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Pharmacokinetic and Pharmacodynamic Evaluation of the Drug‐Drug Interaction Between Isavuconazole and Warfarin in Healthy Subjects

Desai

Yamazaki

Dietz

et al. 2016

Clinical Pharm in Drug Dev

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“…The biological network is comprised of coagulation pathways (extrinsic, intrinsic, and common pathways of clotting), antithrombotic agents, and the mechanism of fibrinolysis 4, 15. The drug‐specific parts include the models for PKs and BKs.…”

Section: Methodsmentioning

confidence: 99%

“…The classic coagulation cascade includes extrinsic, intrinsic, and common pathways, which are assessed by prothrombin time (PT) and activated partial thromboplastin time (aPTT), respectively 4. Factor Xa (FXa) emerged as a promising target for effective anticoagulation because it acts at the convergence point of the intrinsic and extrinsic coagulation pathways.…”

mentioning

confidence: 99%

A Systems Pharmacology Model for Predicting Effects of Factor Xa Inhibitors in Healthy Subjects: Assessment of Pharmacokinetics and Binding Kinetics

Zhou

Huntjens

Gilissen

2015

CPT Pharmacometrics Syst. Pharmacol.

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Factor Xa (FXa) emerged as a promising target for effective anticoagulation and several FXa inhibitors are now available for the prevention of venous thromboembolism. However, in previously reported pharmacokinetic/pharmacodynamic (PK/PD) models, the complex coagulation processes and detailed information of drug action are usually unclear, which makes it difficult to predict clinical outcome at the drug discovery stage. In this study, a large‐scale systems pharmacology model was developed based on several published models and clinical data. It takes into account all pathways of the coagulation network, and captures drug‐specific features: plasma pharmacokinetics and drug‐target binding kinetics (BKs). We aimed to predict the anticoagulation effects of FXa inhibitors in healthy subjects, and to use this model to compare the effects of compounds with different binding properties. Our model predicts the clotting time and anti‐FXa effects and could thus serve as a predictive tool for the anticoagulant potential of a new compound.

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Laboratory Monitoring of Non–Vitamin K Antagonist Oral Anticoagulant Use in Patients With Atrial Fibrillation

et al. 2017

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Robust evidence from patients with atrial fibrillation randomized to NOACs or warfarin demonstrates that unmonitored NOAC therapy is at least as effective and safe as monitored warfarin, with lower rates of intracranial hemorrhage and reduced mortality. Further research is required to determine whether routine laboratory monitoring might provide a net benefit for patients. Until such data are available, clinicians should continue to prescribe NOACs in fixed doses without routine monitoring.

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Oral Anticoagulant Therapy

Abstract: There is a large amount of evidence on laboratory and clinical characteristics of vitamin K antagonists. A growing body of evidence is becoming available on the first new oral anticoagulant drugs available for clinical use, dabigatran and rivaroxaban.

Cited by 1,307 publications

References 378 publications

Pharmacokinetic and Pharmacodynamic Evaluation of the Drug‐Drug Interaction Between Isavuconazole and Warfarin in Healthy Subjects

Pharmacokinetic and Pharmacodynamic Evaluation of the Drug‐Drug Interaction Between Isavuconazole and Warfarin in Healthy Subjects

A Systems Pharmacology Model for Predicting Effects of Factor Xa Inhibitors in Healthy Subjects: Assessment of Pharmacokinetics and Binding Kinetics

Laboratory Monitoring of Non–Vitamin K Antagonist Oral Anticoagulant Use in Patients With Atrial Fibrillation

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