title: Effect of multiple doses of omeprazole on the pharmacokinetics, pharmacodynamics, and safety of a single dose of rivaroxaban.
abstract: Many patients with acute coronary syndrome receive chronic dual antiplatelet therapy (acetylsalicylic acid and clopidogrel) for secondary event prophylaxis, and new oral anticoagulants are being investigated as adjunctive therapy in this indication. Gastrointestinal side effects such as bleeding are commonly associated with antiplatelet use; accordingly, many patients receive proton pump inhibitors (PPIs) to mitigate this. PPIs can reduce the antiplatelet activity of clopidogrel through cytochrome P450 2C19 inhibition, and pantoprazole reduces the bioavailability of dabigatran, a direct thrombin inhibitor that acts via cytochrome P450 2C19-independent mechanisms. These observations support the investigation of potential pharmacokinetic and pharmacodynamic interactions between PPIs and anticoagulants. We evaluated the influence of administering once-daily omeprazole 40 mg for 5 days on the pharmacokinetics and pharmacodynamics of a single 20-mg dose of the oral direct factor Xa inhibitor, rivaroxaban, in a randomized, open-label, 2-way, crossover, drug-drug interaction study in healthy subjects. No clinically meaningful interactions were observed; geometric mean ratios were 101%, 101%, and 93.5% for rivaroxaban area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast), or until infinity (AUC∞), and maximum plasma concentration (Cmax), respectively. Prothrombin time increased similarly in both treatment groups, with maximal values observed approximately 4 hours post rivaroxaban administration. A single 20-mg rivaroxaban dose appears well tolerated when administered alone or after 5 days of once-daily omeprazole 40 mg administration.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, Titusville, NJ 08560, USA. tmoore17@its.jnj.com
authors.forename: Kenneth Todd
authors.initials: KT
authors.lastname: Moore
authors.forename: Alexei Nikolaevich
authors.initials: AN
authors.lastname: Plotnikov
authors.forename: An
authors.initials: A
authors.lastname: Thyssen
authors.forename: Nicole
authors.initials: N
authors.lastname: Vaccaro
authors.forename: Jay
authors.initials: J
authors.lastname: Ariyawansa
authors.forename: Paul Bryan
authors.initials: PB
authors.lastname: Burton
mesh_terms: D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004347:Drug Interactions; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D008297:Male; D009025:Morpholines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D009853:Omeprazole / Q000008:administration & dosage / Q000494:pharmacology*; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000069552:Rivaroxaban; D013876:Thiophenes / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D009025:Morpholines; D054328:Proton Pump Inhibitors; D013876:Thiophenes; D000069552:Rivaroxaban; D009853:Omeprazole