Effect of famotidine on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor

Abstract

BackgroundApixaban is an oral, selective, direct factor Xa inhibitor approved for thromboprophylaxis after orthopedic surgery and stroke prevention in patients with atrial fibrillation, and under development for treatment of venous thromboembolism. This study investigated the effect of a gastric acid suppressant, famotidine (a histamine H2-receptor antagonist), on the pharmacokinetics of apixaban in healthy subjects.MethodsThis two-period, two-treatment crossover study randomized 18 healthy subjects to receive a single oral dose of apixaban 10 mg with and without a single oral dose of famotidine 40 mg administered 3 hours before dosing with apixaban. Plasma apixaban concentrations were measured up to 60 hours post-dose and pharmacokinetic parameters were calculated.ResultsFamotidine did not affect maximum apixaban plasma concentration (Cmax) or area under the plasma concentration-time curve from zero to infinite time (AUC∞). Point estimates for ratios of geometric means with and without famotidine were close to unity for Cmax (0.978) and AUC∞ (1.007), and 90% confidence intervals were entirely contained within the 80%–125% no-effect interval. Administration of apixaban alone and with famotidine was well tolerated.ConclusionFamotidine does not affect the pharmacokinetics of apixaban, consistent with the physicochemical properties of apixaban (lack of an ionizable group and pH-independent solubility). Apixaban pharmacokinetics would not be affected by an increase in gastrointestinal pH due to underlying conditions (eg, achlorhydria), or by gastrointestinal pH-mediated effects of other histamine H2-receptor antagonists, antacids, or proton pump inhibitors. Given that famotidine is also an inhibitor of the human organic cation transporter (hOCT), these results indicate that apixaban pharmacokinetics are not influenced by hOCT uptake transporter inhibitors. Overall, these results support that apixaban can be administered without regard to coadministration of gastric acid modifiers.

Oral Anticoagulant Use After Bariatric Surgery: A Literature Review and Clinical Guidance

“…While an approximately 20% reduction in absorption was seen when dabigatran was given with antacids, this is thought not to be clinically meaningful 15 . The PK of rivaroxaban, apixaban, and edoxaban are not altered by drugs that increase gastric pH 10, 16, 17 .…”

Apixaban: A novel oral inhibitor of factor Xa

“…40 No clinically significant pharmacokinetic interactions were observed when apixaban was coadministered with atenolol, famotidine, digoxin, or naproxen. 40,45,46 Efficacy and safety VTE prophylaxis in major orthopedic surgery. The efficacy and safety of apixaban for VTE prophylaxis in major orthopedic surgery have been evaluated in one Phase II trial and three Phase III trials.…”

Drug Interactions of New Oral Anticoagulants: Inside and Outside Table Cells

“…По мнению ав-торов исследования, ослабление эффекта взаимо-действия обусловлено тем, что верапамил при не-однократном назначении, наряду с ингибированием P-gp, индуцирует экспрессию P-gp в стенках кишечника [13]. Н 2 -блокаторы не влияют [10] не влияют [37] не влияют [36] Ингибиторы протонной помпы от -32% до -12,5% [11,38] не влияют [40] не влияют [41] Иммуносупрессанты Циклоспорин +73% [21] Противоопухолевые Бозутиниб не влияет [43] AUC -area under curve (площадь под кривой концентрация-время); НПВС -нестероидные противовоспалительные средства …”