AimsTo evaluate apixaban single dose safety, tolerability, pharmacokinetics and pharmacodynamics and assess the effect of food on apixaban pharmacokinetics.MethodsA double-blind, placebo-controlled, single ascending-dose, first-in-human study assessed apixaban safety, pharmacokinetics and pharmacodynamics in healthy subjects randomized to oral apixaban (n = 43; 0.5–2.5 mg as solution or 5–50 mg as tablets) or placebo (n = 14) under fasted conditions. An open label, randomized, two treatment crossover study investigated apixaban pharmacokinetics/pharmacodynamics in healthy subjects (n = 21) administered apixaban 10 mg in fasted and fed states. Both studies measured apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and prothrombin time (PT) or a modified PT (mPT).ResultsIn the single ascending-dose study increases in apixaban exposure appeared dose-proportional. Median tmax occurred 1.5–3.3 h following oral administration. Mean terminal half-life ranged between 3.6 and 6.8 h following administration of solution doses ≤2.5 mg and between 11.1 and 26.8 h for tablet doses ≥5 mg. Concentration-related changes in pharmacodynamic assessments were observed. After a 50 mg dose, peak aPTT, INR and mPT increased by 1.2-, 1.6- and 2.9-fold, respectively, from baseline. In the food effect study: 90% confidence intervals of geometric mean ratios of apixaban Cmax and AUC in a fed vs. fasted state were within the predefined no effect (80–125%) range. Apixaban half-life was approximately 11.5 h. The effect of apixaban on INR, PT and aPTT was comparable following fed and fasted administration.ConclusionsSingle doses of apixaban were well tolerated with a predictable pharmacokinetic/pharmacodynamic profile and a half-life of approximately 12 h. Apixaban can be administered with or without food.
Multiple oral doses of apixaban were safe and well tolerated over a 10-fold dose range, with pharmacokinetics with low variability and concentration-related increases in clotting time measures.
Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced stroke and systemic embolism, major bleeding, and mortality. We evaluated treatment effects in relation to 2 predictions of time in therapeutic range (TTR). Methods and Results-The trial randomized 18 201 patients with atrial fibrillation to apixaban 5 mg twice daily or warfarin for at least 12 months. For each patient, a center average TTR was estimated with the use of a linear mixed model on the basis of the real TTRs in its warfarin-treated patients, with a fixed effect for country and random effect for center. For each patient, an individual TTR was also predicted with the use of a linear mixed effects model including patient characteristics as well. Median center average TTR was 66% (interquartile limits, 61% and 71%). Rates of stroke or systemic embolism, major bleeding, and mortality were consistently lower with apixaban than with warfarin across center average TTR and individual TTR quartiles. In the lowest and highest center average TTR quartiles, hazard ratios for stroke or systemic embolism were 0.73 (95% confidence interval [CI], 0.53-1.00) and 0.88 (95% CI, 0.57-1.35) (P interaction =0.078), for mortality were 0.91 (95% CI, 0.74-1.13) and 0.91 (95% CI, 0.71-1.16) (P interaction =0.34), and for major bleeding were 0.50 (95% CI, 0.36-0.70) and 0.75 (95% CI, 0.58-0.97) (P interaction =0.095), respectively. Similar results were seen for quartiles of individual TTR.© 2013 American Heart Association, Inc.Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.112.142158Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz. W arfarin and other vitamin K antagonists effectively prevent stroke in patients with atrial fibrillation (AF), but they have a narrow therapeutic window with an increased risk of stroke and bleeding when above or below the therapeutic range of the international normalized ratio (INR) of 2.0 to 3.0.1-3 The dose response is influenced by several factors such as age, body weight, genetic variation, food, and comedications. Regular INR-guided dose adjustments are therefore necessary.1-3 However, there are large variations of the time in therapeutic range (TTR) across individuals, sites, and countries, and these variations are related to patient outcomes. [4][5][6][7][8][9] Several trials have shown recently that the quality of warfarin use, as measured with INR control at the center or country level, may interact with the treatment effects of new antithrombotic treatments when compared with warfarin. 10-12 Editorial see p 2163 Clinical Perspective on p 2176Apixaban is a new oral direct factor Xa inhibitor providing stable anticoagulation at a fixed dose twice daily without the need for anticoagulation monitoring. In the prospective, randomized, and double-blind Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial including 18 201 patients with AF and at least 1 additiona...
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