New anticoagulants for prevention of stroke in patients with atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac rhythm disorder and a major risk factor for ischemic stroke. Antithrombotic therapy using vitamin K antagonists (VKA) is currently prescribed for prevention of ischemic stroke in patients with AF. A narrow therapeutic range and frequent food and drug interactions underly the need for regular monitoring of anticoagulation intensity and impairs the utility and safety of VKA, stimulating a quest for alternative anticoagulant agents. Recently developed anticoagulants include the direct thrombin inhibitor, dabigatran, and the factor Xa inhibitors rivaroxaban, apixaban, edoxaban, to name those in the most advanced stages of clinical development. This review focuses on advances in the development of novel antithrombotic agents to provide practical information to clinicians on the use of these new drugs in patients with AF.     

达比加群酯的合成工艺改进

目的 改进达比加群酯的合成工艺,提高反应收率并简化操作。方法 以4-甲胺基-3-硝基苯甲酸为原料,与3-（吡啶-2-基氨基）丙酸乙酯缩合后,经催化氢化、酰胺化后闭环、成脒、与氯甲酸正己酯反应得到达比加群酯。结果与结论 目标化合物的结构经核磁共振氢谱、质谱确证。改进后的合成方法与原工艺相比,环境友好,收率提高了16.4%,总收率为33.75%(以4-甲胺基-3-硝基苯甲酸计)。     

Phase III studies on novel oral anticoagulants for stroke prevention in atrial fibrillation: a look beyond the excellent results

Summary. In this overview we address the three phase III studies that compared new oral anticoagulants (dabigatran, rivaroxaban and apixaban) with warfarin in the setting of stroke prevention in atrial fibrillation. Strengths and weaknesses of the studies were examined in detail through indirect comparison. We analyze and comment the inclusion and exclusion criteria, the characteristics of randomized patients, the primary efficacy and safety end points and side effects. All new oral anticoagulants resulted in being non‐inferior to vitamin K antagonists in reducing stroke or systemic embolism in patients with atrial fibrillation. Dabigatran 150 mg and apixaban were superior to vitamin K antagonists. Importantly, new oral anticoagulants significantly reduced hemorrhagic stroke in all three studies. Major differences among new oral anticoagulants include the way they are eliminated and side effects. Both dabigatran and apixaban were tested in low‐ to moderate‐risk patients (mean CHADS2 [Congestive heart failure, Hypertension, Age, Diabetes, Stroke] score = 2.1–2.2) whereas rivaroxaban was tested in high‐risk patients (mean CHADS2 score = 3.48) and at variance with dabigatran and apixaban was administered once daily. Apixaban significantly reduced mortality from any cause. The choice of a new oral anticoagulant should take into account these and other differences between the new drugs.     

Drug interactions between direct-acting oral anticoagulants and calcineurin inhibitors during solid organ transplantation: considerations for therapy

ABSTRACT

Introduction: There is a high incidence of venous thromboembolism (VTE) in solid organ transplant recipients. The safety and efficacy of direct-acting oral anticoagulants (DOAC) have been well established in clinical practice for the prevention and treatment of VTE in broad populations. However, the management of VTE in the setting of solid organ transplantation remains a challenge to clinicians due to limited evidence of DOAC usage with calcineurin inhibitors.

Areas covered: The current literature available on the pharmacokinetic–pharmacodynamic interaction between DOACs and calcineurin inhibitors is presented. A comprehensive review was undertaken using PubMed, Embase, drug product labeling, and drug product review conducted by the US Food and Drug Administration using Drugs@FDA. The potential for mitigation strategies and clinical management using extant knowledge is explored.

Expert opinion: Immunosuppression therapy is necessary to prevent graft rejection by the host. The sparsity of data together with the lack of well-designed prospective studies of DOAC use in solid organ transplant recipients presents a unique challenge to clinicians in determining the clinical relevance of possible drug interactions. Existing evidence suggests that with attention to concomitant drug use and renal function, the co-administration of DOACs and calcineurin inhibitors is safe and effective.     

A semi-mechanistic absorption model to evaluate drug–drug interaction with dabigatran: application with clarithromycin

Aim

The aim of this study was to develop a PK/PD model to assess drug–drug interactions between dabigatran and P-gp modulators, using the example of clarithromycin, a strong inhibitor of P-gp.

Methods

Ten healthy male volunteers were randomized to receive in the first treatment period a single 300 mg dose of dabigatran etexilate (DE) and in the second treatment period 500 mg clarithromycin twice daily during 3 days and then 300 mg DE plus 500 mg clarithromycin on the fourth day, or the same treatments in the reverse sequence. Dabigatran plasma concentration and ecarin clotting time (ECT) were measured on 11 blood samples. Models were built using a non-linear mixed effect modelling approach.

Results

The best PK model was based on an inverse Gaussian absorption process with two compartments. The relationship between dabigatran concentration and ECT was implemented as a linear function. No continuous covariate was associated with a significant decrease in the objective function. The concomitant administration of clarithromycin induced a significant change only in DE bioavailability, which increased from 6.5% to 10.1% in the presence of clarithromycin. Clarithromycin increased peak concentration and AUC by 60.2% and 49.1% respectively.

Conclusion

The model proposed effectively describes the complex PK of dabigatran and takes into account drug–drug interactions with P-gp activity modulators, such as clarithromycin.