Absolute bioavailability and regional absorption of ticagrelor in healthy volunteers

Abstract

Objective:

Ticagrelor is a direct-acting, reversibly-binding, oral P2Y₁₂ receptor antagonist. It demonstrates predictable, linear pharmacokinetics. Two studies were undertaken to further elucidate the absolute bioavailability of ticagrelor and its regional absorption in the gastrointestinal (GI) tract.

Design and methods:

In two open-label, randomized, cross-over studies, 12 volunteers received a single dose of ticagrelor: oral 90 mg and 15 mg IV (Study 1); or 100 mg oral suspension vs 100 mg immediate release (IR) tablet (Study 2). After the initial cross-over period in Study 2, patients received 100 mg suspension delivered to specific sites in the GI tract using an Enterion capsule. In both studies, plasma concentrations of ticagrelor and AR-C124910XX were measured following administration of each formulation.

Results:

The mean absolute bioavailability of ticagrelor was 36% (95% confidence interval = 30–42%). Metabolite:parent ratios were higher after oral administration, compared with IV administration (maximum plasma concentration [C_max] = 0.356 and 0.037; area under the plasma concentration-time curves [AUC] = 0.530 and 0.173, respectively). Following oral administration of the 100 mg IR tablet, the AUC and C_max of ticagrelor were 78% and 58%, respectively, of those following oral administration of the 100 mg suspension. Exposure to ticagrelor decreased the further down the GI tract it was released: mean C_max for ticagrelor was 91%, 68%, and 13% that for the oral suspension when released in the proximal small bowel, distal small bowel and ascending colon, respectively; mean AUCs were 89%, 73%, and 32%, respectively.

Conclusion:

The mean absolute bioavailability of ticagrelor was 36% and the proportion of ticagrelor absorbed decreased the further down the GI tract it was released: the mean AUC for ticagrelor was 89% (proximal small bowel), 73% (distal small bowel), and 32% (ascending colon) that of the mean AUC for the orally administered suspension.

Keywords::

• Absolute bioavailability
• Regional absorption
• P2Y₁₂ receptor antagonist
• Ticagrelor

Transparency

Declaration of funding

This study was sponsored by AstraZeneca (Alderley Park, Cheshire, UK).

Declaration of financial/other interests

Renli Teng and Juan Maya are employees of AstraZeneca. JDA Peer reviewers on this manuscript have no relevant financial relationships to disclose.

Acknowledgments

The authors would like to thank Clare Ryles and David Evans (Gardiner-Caldwell Communications) who provided medical writing support, funded by AstraZeneca.