A phase II trial is being conducted at an academic medical center to assess the safety and efficacy of a novel antifungal medication that has yielded promising results in preclinical studies. The medication is known to inhibit fungal colony growth by changing the composition of the fungal cell membrane. Phase 0 and phase I trials on healthy volunteers have been uneventful. The current phase II trial includes 175 subjects. In 168 subjects, the new antifungal agent is found to inhibit liver cytochrome P450-dependent metabolism of several drugs. Based on these data, the new antifungal agent is most similar to which of the following?

Question

A phase II trial is being conducted at an academic medical center to assess the safety and efficacy of a novel antifungal medication that has yielded promising results in preclinical studies.  The medication is known to inhibit fungal colony growth by changing the composition of the fungal cell membrane.  Phase 0 and phase I trials on healthy volunteers have been uneventful.  The current phase II trial includes 175 subjects.  In 168 subjects, the new antifungal agent is found to inhibit liver cytochrome P450-dependent metabolism of several drugs.  Based on these data, the new antifungal agent is most similar to which of the following?

Quizplus · Accepted Answer

Azoles are antifungal medications that inhibit the demethylation of lanosterol into ergosterol in fungal cells. They exert their antifungal effects by suppressing synthesis of ergosterol, an essential component of the fungal cell membrane. However, azoles also inhibit the activity of the human P450 cytochrome oxidase system. This property leads to multiple drug-drug interactions. All azoles (eg, ketoconazole, fluconazole, itraconazole, voriconazole) increase the serum concentrations of drugs metabolized by liver P450 enzymes. This means that, when used concomitantly with azoles, drugs metabolized by the liver P450 system may have increased toxicity. For this reason, medications such as warfarin, cyclosporine, tacrolimus, and oral hypoglycemics should be avoided (or have their use carefully monitored) in patients who are receiving azole therapy. Cytochrome oxidase inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital) increase azole metabolism, thereby lowering azole concentration in serum. (Choice A) Amphotericin B is a polyene antifungal that binds ergosterol in the fungal cell membrane, leading to pore formation and cell lysis. (Choice B) 1,3-beta-D-glucan is a major polysaccharide component of the fungal cell wall. Caspofungin and the other echinocandin antifungals block glucan synthesis. (Choice C) Flucytosine inhibits the synthesis of both DNA (replication) and RNA (protein synthesis) in fungal cells. It is mainly used as a synergistic agent with amphotericin B. This drug combination is particularly important in the treatment of cryptococcal meningitis. (Choice D) Griseofulvin, a P450 inducer, enters fungal cells and binds microtubules, inhibiting mitosis. Educational objective: Azoles inhibit the synthesis of ergosterol by the fungal cytochrome P450 enzymes. They also suppress the human P450 system, resulting in many drug-drug interactions.

A Phase II Trial Is Being Conducted at an Academic