An Emerging Extended-Spectrum Triazole Antifungal: Noxafil® (Posaconazole)

Special Feature (Part 2 of 2)

By Jean Yong Nam, PharmD Candidate, Rehan Noori, PharmD Candidate, and Jessica C. Song, MA, PharmD, Jean Yong Nam and Rehan Noori are PharmD Candidates at the University of the Pacific School of Pharmacy, and Jessica C. Song is Pharmacy Residency Coordinator, Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA, Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert.

Jean Yong Nam, Rehan Noori, and Jessica C. Song report no financial relationship relevant to this field of study.

Comparisons of Antifungals

Posaconazole exhibits numerous advantages over other triazoles in regards to drug-drug interactions, bioavailability issues, and its side-effect profile. As seen in Table 5, unlike various triazoles, posaconazole does not inhibit the majority of cytochrome P450 isoenzymes, with only marginal inhibition of CYP 3A4.3,5,8

Posaconazole offers an advantage over other triazoles, especially in critically ill patients who require acid suppression for stress-related mucosal damage prevention. A study by Courtney and colleagues showed that unlike ketoconazole and itraconazole, changes in pH have a clinically insignificant effect on posaconazole absorption, resulting in a broad-spectrum antifungal with predictable absorption regardless of gastric pH.2

At present, one echinocandin, caspofungin, is FDA-approved for use in the treatment of invasive Aspergillosis refractory to standard therapy.26 A recent update of a pivotal study demonstrated a success (complete or partial response) rate of 45% with caspofungin therapy.27 This is nearly the same success rate demonstrated for posaconazole in the salvage setting.5

Posaconazole has been reported to be effective in some cases of zygomycosis, as demonstrated by a success (complete or partial response) rate of 60% in one retrospective report. Of note, 20% of the patients included in this report received voriconazole prior to experiencing breakthrough zygomycosis. Survival rates of 61% and 69% have been observed in Zygomycetes-infected patients treated with amphotericin B deoxycholate and lipid-associated formulations of amphotericin B, respectively.21

Current guidelines from the Infectious Disease Society of America recommend the use of topical agents (clotrimazole troches, nystatin) or fluconazole for treatment of initial episodes of oropharyngeal candidiasis.28 Results of a recent trial indicate that posaconazole is equivalent in efficacy to fluconazole for the treatment of oropharyngeal Candidiasis, but is more effective in prolonging mycologic success. Both micafungin and posaconazole have been studied in the prophylaxis of IFIs in HSCT patients. Micafungin was shown to have a superior overall treatment success compared with fluconazole (P = 0.03),26 whereas, success rates trended in favor of posaconazole (P = 0.074).4 See Table 4, which outlines the key data regarding the efficacy of posaconazole in patients with oropharyngeal candidiasis and in patients with zygomycosis.

Conclusion

Posaconazole represents a new and exciting drug for the treatment of numerous opportunistic invasive fungal infections caused by pathogens such as Aspergillus spp, Candida spp, Fusarium spp, and Zygomycetes spp. Efficacy of posaconazole is comparable to caspofungin (salvage therapy for invasive aspergillosis), fluconazole (oropharyngeal candidiasis) and amphotericin B deoxycholate/lipid formulations (zygomycosis), with the advantage of significantly fewer side effects and drug-drug interactions.

Currently, posaconazole is the only triazole antifungal agent that has demonstrated activity against Zygomycetes, a pathogen that is usually eradicated with amphotericin B. Moreover, unlike the echinocandins (caspofungin, micafungin, anidulafungin), which are only available as parenteral agents, posaconazole is able to be administered orally (ingestion and through nasogastric tube). If FDA approval is granted, posaconazole likely will be prescribed for prophylaxis of IFIs in patients who are at high risk of acquiring these infections, treatment of refractory invasive aspergillosis, treatment of non-albicans oropharyngeal candidiasis, and some zygomycosis.

References

  • References 1-20 can be found in Part I of this article printed in the June 2006 issue of Infectious Disease Alert.
  1. van Burik JA, et al. Posaconazole is Effective as Salvage Therapy in Zygomycosis: A Retrospective Summary of 91 Cases. Clin Infect Dis. 2006;42:e61-e65.
  2. Courtney R, et al. Effect of Food on the Relative Bioavailability of Two Oral Formulations of Posaconazole in Healthy Adults. Br J Clin Pharmacol. 2004;57:218-222.
  3. Krieter P, et al. Disposition of Posaconazole Following Single-Dose Oral Administration in Healthy Subjects. Antimicrob Agents Chemother. 2004;48:3543-3551.
  4. Ezzet F, et al. Oral Bioavailability of Posaconazole in Fasted Healthy Subjects: Comparison Between Three Regimens and Basis for Clinical Dosage Recommendations. Clin Pharmacokinet. 2005;44:211-220.
  5. PR Newswire. Schering-Plough reports Noxafil® NDA Granted FDA 6-Month Priority Review for Prevention of Invasive Fungal Infections. sev.prnewswire.com/medical-pharmaceuticals/20060222/NYW06022022006-1.html.
  6. Song JC, et al. Micafungin (Mycamine®). Infectious Disease Alert. 2005;25:30-34.
  7. Maertens J, et al. Update of the Multicenter Noncomparative Study of Caspofungin (CAS) in Adults with Invasive Aspergillosis Refractory or Intolerant to Other Antifungal Agents: Analysis of 90 Patients [abstract no. M-868]. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) Abstracts, American Society for Microbiology; 2002 Sep 27-30; San Diego
  8. Pappas PG, et al. Guidelines for Treatment of Candidiasis. Clin Infect Dis. 2004;38:161-189.