Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects.
To investigate the influence of food and administration of an antacid (aluminum-magnesium hydroxide) or ranitidine on the absorption of BAY 59-7939 (rivaroxaban), 4 randomized studies were performed in healthy male subjects. In 2 food interaction studies, subjects received BAY 59-7939, either as two 5-mg tablets (fasted and fed), four 5-mg tablets (fasted), or one 20-mg tablet (fasted and fed). In 2 drug interaction studies, BAY 59-7939 (six 5-mg tablets) was given alone or with ranitidine (150 mg twice daily, preceded by a 3-day pretreatment phase) or antacid (10 mL). Plasma samples were obtained to assess pharmacokinetic and pharmacodynamic parameters of BAY 59-7939. In the presence of food, time to maximum concentration (t(max)) was delayed by 1.25 hours; maximum concentration (C(max)) and area under the curve (AUC) were increased, with reduced interindividual variability at higher doses of BAY 59-7939. Compared with baseline, BAY 59-7939 resulted in a relative increase in maximum prothrombin time (PT) prolongation of 44% (10 mg) and 53% (20 mg) in the fasted state, compared with 53% and 83% after food. Time to maximum PT prolongation was delayed by 0.5 to 1.5 hours after food, with no relevant influence of food type. No significant difference in C(max) and AUC was observed with coadministration of BAY 59-7939 and ranitidine or antacid.
Kubitza
Dagmar
D
Institute of Clinical Pharmacology, Bayer HealthCare AG, Wuppertal, Germany. dagmar.kubitza@bayerhealthcare.com
Becka
Michael
M
Zuehlsdorf
Michael
M
Mueck
Wolfgang
W
D000328:Adult; D000536:Aluminum Hydroxide / Q000494:pharmacology; D000863:Antacids / Q000494:pharmacology*; D018592:Cross-Over Studies; D004040:Dietary Carbohydrates / Q000494:pharmacology; D004041:Dietary Fats / Q000494:pharmacology; D004338:Drug Combinations; D004347:Drug Interactions; D065427:Factor Xa Inhibitors; D005215:Fasting / Q000378:metabolism; D018565:Food-Drug Interactions; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D008276:Magnesium Hydroxide / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011517:Prothrombin Time; D011899:Ranitidine / Q000494:pharmacology*; D000069552:Rivaroxaban; D013876:Thiophenes / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
D000863:Antacids; D004040:Dietary Carbohydrates; D004041:Dietary Fats; D004338:Drug Combinations; D065427:Factor Xa Inhibitors; D006635:Histamine H2 Antagonists; D009025:Morpholines; D013876:Thiophenes; C013591:aluminum hydroxide, magnesium hydroxide, drug combination; D000536:Aluminum Hydroxide; D011899:Ranitidine; D000069552:Rivaroxaban; D008276:Magnesium Hydroxide