Evaluation of Crushed Tablet for Oral Administration and the Effect of Food on Apixaban Pharmacokinetics in Healthy Adults

Clin Ther. 2016 Jul;38(7):1674-1685.e1. doi: 10.1016/j.clinthera.2016.05.004. Epub 2016 Jun 10.

Abstract

Purpose: These studies evaluate the relative bioavailability of crushed apixaban tablets and the effect of food on apixaban pharmacokinetic properties.

Methods: An open-label, randomized, crossover study in 33 healthy adults compared the bioavailability of 2 × 5-mg apixaban tablets administered whole (reference), crushed and suspended in 30 mL of water, and crushed and mixed with 30 g of applesauce. A second open-label, randomized, crossover study in 22 healthy adults compared apixaban 1 × 5-mg tablet administered when fasted (reference) or immediately after consumption of a high-fat, high-calorie meal. Point estimates and 90% CIs for geometric mean ratios were generated for Cmax, AUC0-∞, and AUC0-t.

Findings: Cmax and AUC met bioequivalence criteria for crushed tablets in water. Cmax and AUC decreased by 21.1% and 16.4%, respectively, with the lower bound of the CIs falling below the bioequivalence criteria for crushed tablets with applesauce. Similarly, administration of whole tablets with a high-fat, high-calorie meal reduced apixaban Cmax and AUC by 14.9% and 20.1%, respectively. The exposure reductions in both studies were considered not clinically significant.

Implications: Apixaban tablets can be administered crushed or whole, with or without food. The results of these alternative methods of administration support their use in patients who have difficulty swallowing tablets. ClinicalTrials.gov identifiers: NCT02101112 and NCT01437839.

Keywords: apixaban; bioavailability; crushed tablet; food effect; formulation; stability.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Adult
  • Biological Availability
  • Cross-Over Studies
  • Drug Stability
  • Factor Xa Inhibitors / pharmacokinetics*
  • Fasting
  • Female
  • Food-Drug Interactions*
  • Humans
  • Male
  • Pyrazoles / pharmacokinetics*
  • Pyridones / pharmacokinetics*
  • Tablets
  • Therapeutic Equivalency

Substances

  • Factor Xa Inhibitors
  • Pyrazoles
  • Pyridones
  • Tablets
  • apixaban

Associated data

  • ClinicalTrials.gov/NCT02101112
  • ClinicalTrials.gov/NCT01437839