Thursday, November 07, 2013

Novel (target specific) oral anticoagulants: pharmacokinetics and drug interactions

This post contains some more of the key points from Dr. Tracy Minichiello's talk at the recent UCSF Hospital Medicine conference along with additional material I've gathered including this review.

First a little background about CYP3A4 and P glycoprotein. CYP3A4 is an important enzyme affecting drug bioavailability and metabolism. Drugs (including the TSOACs) and food (notably grapefruit) may interact via CYP3A4. Unfortunately comprehensive lists of interacting drugs are difficult to find and popular consumer resources may not be updated concerning the TSOACs. I did find this article helpful (click on the pdf link for free full text). It is a bit dated but does contain a long list of applicable drugs. Given the lack of current and comprehensive references your best bet may be to use one of the on line interaction checkers such as the one available via UpToDate.

P glycoprotein is the other big player. P glycoprotein is an ATP-binding cassette (ABC) transporter which extrudes substances out of cells and thus plays a role in drug disposition and bioavailability. All three currently approved TSOACs are susceptible to interactions involving the protein. Again, because comprehensive lists of interacting drugs are not readily available the use of an interaction checker may be necessary. Some background can be found in this paper.

Below are a few of the basics about the kinetics of available TSOACs.

Routes of elimination:

Dabigatran (Pradaxa) 80% renal
Rivaroxaban (Xarelto) 30-60% renal (60% total but half of this is of an inactive metabolite).
Apixaban (Eliquis) 25% renal

Degree of protein binding:

Dabigatran (Pradaxa) 33% (HD effective for removal)
Rivaroxaban (Xarelto) 95% (HD ineffective for removal)
Apixaban (Eliquis) 87% (HD ineffective for removal)

Drug interactions:

Dabigatran (Pradaxa) Via P glycoprotein
Riaroxaban (Xarelto) Via P glycoprotein and CYP3A4
Apixaban (Eliquis) Via P glycoprotein and CYP3A4

Though focused on pulmonary embolism this review is also helpful concerning some of the general aspects of the pharmacokinetics and pharmacodynamics of TSOACs.

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