Answer 1: False
While unbound (i.e. “free”) warfarin concentrations may be transiently increased with the addition of a concomitant highly protein bound drug, “free” drug concentrations return to baseline levels relatively quickly due to the elimination of additional unbound drug.
A review of the US Prescribing Information2 indicates clinically significant drug interactions with warfarin may result via pharmacodynamic mechanisms (e.g. concomitant drugs that cause bleeding risk, such as antiplatelet drugs) or via pharmacokinetic interactions by induction or inhibition of CYP2C9, CYP1A2, and/or CYP3A4 isoenzymes.
Answer 2: B
This is a 2-way pharmacokinetic interaction, whereby both bosentan and glyburide concentrations are reduced, likely due to induction of CYP3A and CYP2C9 enzymes by each agent.1 Consequently, efficacy may be compromised for both agents during co-administration.
Answer 3: False
Decreased systemic exposure of drug due to a pharmacokinetic interaction typically results in loss of efficacy, not increased risk of toxicity.
The observed pharmacodynamic interaction (increased risk of liver enzyme elevations) cannot be readily explained by the pharmacokinetic interaction in this case. Alternative hypotheses for the liver enzyme effects include potential inhibition of bile salt export pump (BSEP) by both bosentan and glyburide, which results in increased hepatocyte concentrations of toxic bile salts, or potential formation of a reactive metabolite.3
Answer 4: E (A and C)
As the compound is metabolized primarily by CYP3A and partially by CYP2C19, important DDI studies would include a study with itraconazole (strong CYP3A inhibitor) and fluconazole (strong CYP2C19 inhibitor). Fluconazole is also a moderate inhibitor of CYP3A, and thus would provide a good characterization of the “worst case” effect for CYP2C19 + CYP3A inhibition. Fluconazole is also a widely used antifungal agent, and therefore would provide useful information for a product intended to be used by a wide patient population.
In addition to characterizing the impact of perpetrator drugs on the compound, it is also necessary to characterize the effect of the compound as a potential inhibitor of P-gp. Digoxin is typically used characterize the effect of a potential perpetrator on P-gp. Digoxin would also be a potential co-medication in a population of patients with diabetes or high blood pressure, and therefore would be an important drug to study with this compound.
A midazolam DDI study is not necessary, as the compound is not a potential inducer or inhibitor of CYP3A.
References:
- TRACLEER® (bosentan) US Prescribing Information, 10/2012. Actelion Pharmaceuticals US, Inc. South San Francisco, CA, USA
- COUMADIN® (warfarin) US Prescribing Information, 10/2011. Bristol-Myers Squibb Company, Princeton, New Jersey, USA.
- van Giersbergen PLM, Treiber A, Clozel M, Bodin F, Dingemanse J. Clin Pharmacol Ther. 2002;71(4):253-62.
Presented by the PhRMA Foundation Safe and Effective Prescribing Project
For more information, please call 202-572-7756
