MIAMI — The echinocandin antifungal agents appear to have little significant toxicity and may ultimately prove to be safer than the azoles or amphotericin B in terms of potential interactions, according to Paul O. Gubbins, Pharm.D.
“Echinocandins are an exciting new class. To date, there are few significant drug-drug interactions,” Dr. Gubbins said at a meeting on fungal infections sponsored by Imedex.
The echinocandin caspofungin (Cancidas) has “no significant interaction” with cytochrome P-450 (CYP450) metabolism or P-glycoprotein, according to product labeling. The most abundant enzyme in the CYP450 system, CYP3A4, metabolizes about 50%-60% of all medicines.
In addition, the recently approved echinocandin micafungin (see accompanying story) is not a substrate or inhibitor for P-glycoprotein, a transmembrane efflux pump in the liver, intestine, kidneys, and blood-brain barrier.
With a lower potential for interactions, the echinocandins may be ideal for combination therapy, said Dr. Gubbins, chair of the department of pharmacy practice, University of Arkansas, Little Rock.
Toxicity is another important consideration, and it can relate to drug interactions. Traditional formulations of amphotericin B have renal toxicity that can produce additive drug interactions. “We're all familiar with the toxicities of amphotericin B. They are subtle and, in most cases, unavoidable. Consider renal-sparing alternatives” such as lipid amphotericin B or caspofungin, he suggested.
When prescribing traditional amphotericin B, monitor serum levels of drugs that have a narrow therapeutic index and are eliminated by the kidneys. Examples include aminoglycosides and 5-flucytosine.
Physicians are much more aware of drug interactions now than they used to be, and not just for antifungals, but for all drug classes, Dr. Gubbins said in response to a meeting attendee's question.
Some patients, such as organ transplant recipients, require closer monitoring. They often use drugs they cannot avoid, such as immunosuppressants, which increase the risk of fungal infections, he added.
The azoles have a complicated set of interactions. They can interact through multiple mechanisms, including CYP450 metabolism, gastric pH-dependent effects, and P-glycoprotein activity. “Interactions can be managed with alternative drugs in the affected class or by switching agents,” Dr. Gubbins said.
Itraconazole leads the azole class in terms of p otential interactions. The antifungal interacts through the CYP450 system with statins, especially lovastatin, simvastatin, and atorvastatin (Lipitor), and this can lead to skeletal muscle toxicity. Other affected agents include benzodiazepines, anxiolytics, immunosuppressants, and corticosteroids. With corticosteroids, he said, “The key is, it doesn't matter if you give these orally or IV, or if they're inhaled, you can get interactions.”
Itraconazole can also have significant pH interactions. Dissolution depends on gastric pH, meal composition, and gastric emptying. Dr. Gubbins suggested that patients take the tablets with a high-fat meal that is dense in calories in order to slow gastric emptying or with a meal that contains enough protein to buffer the stomach contents. Other techniques for reducing pH interactions include spacing the administration of tablets, considering itraconazole oral solution, or switching to another agent. P-glycoprotein interactions are significant only for itraconazole, not for voriconazole (Vfend), or fluconazole, Dr. Gubbins said.
Although several agents lower serum levels of itraconazole, including phenytoin, phenobarbital, rifampin, and rifabutin (Mycobutin), “remember that itraconazole affects other medications more than other medications affect itraconazole,” he said. “The ones we're worried about are the ones with a narrow therapeutic index, such as digoxin.”
Fluconazole affects more CYP450 enzymes than does itraconazole. “It's a whole different ball game,” Dr. Gubbins said. Interactions depend largely on fluconazole concentration and are typically seen with doses greater than 200 mg.
Of particular concern are interactions between fluconazole and phenytoin or warfarin. “With phenytoin, if you do not see a response, it could be that [phenytoin] is inhibiting fluconazole.”
“We also worry about the anticoagulant warfarin. … This interaction is almost guaranteed.” Decreasing the warfarin dose might help, but “you almost always need to move to another antifungal.”
Three CYP450 enzymes metabolize voriconazole extensively. Two have genetic polymorphisms that make interactions more likely in certain populations. For example, a CYP2C19 polymorphism is present in 2%-5% of whites, 12%-23% of Asians, and 38%-79% of South Pacific populations.
Drugs that affect voriconazole include phenytoin, rifampin, and rifabutin. Other potential interactions include carbamazepine, protease inhibitors, nonnucleoside reverse transcriptase inhibitors, benzodiazepines, and statins.
“How do we get around this? There are drugs we just don't use with voriconazole, such as rifampin or rifabutin,” Dr. Gubbins said. He also suggested increasing the voriconazole dosage cautiously with phenytoin and monitoring patients taking warfarin closely.