MORE @ WWW. PHARMACY For references, go to www RX FOCUS DRUG INTERACTIONS TIMES.COM .PharmacyTimes.com/ publications/issue. Enzyme Inducer Plus Enzyme Inhibitor: What Will Happen? John R. Horn, PharmD, FCCP, and Philip D. Hansten, PharmD

CYP2D6, CYP3A4, and p-glycoprotein. navir, midazolam AUC was less than 5% Based on these assumptions, there are of that seen during concurrent St. John’s John R. Horn, PharmD, FCCP several potential interactions that could wort and ritonavir and was less than 25% occur when amiodarone and bosentan are of the midazolam AUC at baseline. coadministered: This study demonstrates that during the 1. Bosentan could induce amiodarone concurrent administration of St. John’s metabolism via CYP3A4. This could wort and ritonavir, the predominant effect lead to reduced antiarrhythmic efficacy is enzyme inhibition. When both drugs of amiodarone. were discontinued, the induction effect of 2. Amiodarone could inhibit bosen- St. John’s wort appeared to be present 2 tan metabolism via CYP3A4 and/or days later, whereas the inhibition of ritona- Philip D. Hansten, PharmD CYP2C9. Increased bosentan response vir had ceased. or side effects may occur. This raises In another study of the effect of rifampin the question of what outcome might be on lopinavir-ritonavir combination therapy, expected when the induction of CYP3A4 increasing the dose of lopinavir-ritonavir (via bosentan) is combined with the inhi- by only 2-fold resulted in a more than bition of CYP3A4 (via amiodarone). 6-fold increase in lopinavir levels, indicat- ing that a larger dose of ritonavir produced Are There Related Data to a greater increase in lopinavir concentra- Inhibitor Plus Inducer: Therein Consider? tion than would have been expected from Lies the Question Recently a study was done to examine the doubling the lopinavir dose.2 Ritonavir has We often get questions from practitio- effects of ritonavir (a CYP3A4 inhibitor) also been shown to counteract the enzyme- ners seeking help with the management and St. John’s wort (a CYP3A4 inducer) inducing activity of efavirenz (Sustiva) and of potential drug interactions. A recent alone and in combination on the metab- etravirine (Intelence).3,4 inquiry asked what might be the result of olism of midazolam.1 Twelve subjects the concurrent administration of amioda- received single oral doses of midazolam Summary rone (Cordarone) and bosentan (Tracleer). alone and with single doses of St. John’s It would appear that when potent enzyme Because we were unable wort 300 mg or ritonavir inhibitors are combined with potent induc- to find any studies of this During the con- 300 mg. Midazolam was ers, the inhibition will tend to predomi- interaction, we can start by again administered after St. nate. Unlike inhibitors where the inhibi- assessing what we know current admin- John’s wort 300 mg 3 times tory activity often abates when the drug is about the interaction poten- a day plus ritonavir 100 mg discontinued, recovery from induction may tial of each drug. istration of St. twice a day were adminis- take several days following the withdrawal tered for 14 days. A third of the inducer. What Do We Know? John’s wort and dose of midazolam was Upon discontinuation of the drugs, be Bosentan is a substrate of given 2 days after ritonavir alert for a rapid shift to induction and cytochrome P450 (CYP) ritonavir, the and St. John’s wort were potential reduction in object drug effect. 3A4 and CYP2C9. It is predominant discontinued. As always, patient monitoring with appro- also known to be an inducer The area under the priate drug dose adjustment is extremely of CYP3A4 and CYP2C9 effect is enzyme concentration time curve important with these complex interactions. and may induce other iso- (AUC) of midazolam was enzymes as well. Thus, it inhibition. unaffected by a single dose would be expected to induce of St. John’s wort but was its own metabolism with chronic dosing, increased about 5-fold following single- and steady-state plasma concentrations dose ritonavir. After 14 days of combined Drs. Horn and Hansten are both professors have been noted to be reduced to 50% to St. John’s wort and ritonavir, the AUC of of pharmacy at the University of Washington 60% of single-dose levels. midazolam was similar to that seen with School of Pharmacy. For an electronic version Amiodarone is a substrate of CYP3A4 ritonavir alone. Two days following the of this article, including references if any, visit www.hanstenandhorn.com. and CYP2C8 and an inhibitor of CYP2C9, discontinuation of St. John’s wort and rito-

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