An Emerging Extended-Spectrum Triazole Antifungal: Noxafil® (Posaconazole)
Special Feature (Part 1 of 2)
By Jean Yong Nam, PharmD Candidate, Rehan Noori, PharmD Candidate, and Jessica 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.
Introduction
Medical advances in recent years have resulted in an increased frequency of invasive fungal infections.1 Patients undergoing solid organ transplantation, HIV/AIDS treatment, and invasive surgical procedures are especially susceptible to fungal pathogens, and are more likely to experience recurrent fungal infections.2,3 Within the past 2 decades, escalating morbidity/mortality rates have been associated with Aspergillus and Candida infections among immunocompromised patients undergoing hematopoietic stem cell transplants.4 Similarly, previously uncommon fungal infections such as Fusariosis and Zygomycosis are now becoming more prevalent, further supporting the need for newer, well-tolerated antifungal agents that demonstrate efficacy against these invasive and refractory fungal infections.1,5
Despite the availability of numerous antifungal agents, treatment options for invasive fungal infections are often limited by tolerability issues, and the potential for drug-drug interactions and resistance. Amphotericin B is the preferred antifungal for a variety of fungal infections, but its use is limited by its potential to induce nephrotoxicity.6 In addition, resistance to fluconazole has been increasingly noted, and other triazoles, such as voriconazole and itraconazole interact with numerous drugs.3,5 The risk of drug interactions is especially increased in the immunocompromised, who often receive multiple medications.7,8 The medications in the echinocandin class (eg, caspofungin) also have limitations because they are only available as intravenous formulations, which restricts outpatient utilization.5
Posaconazole is a second-generation extended-spectrum triazole antifungal agent, that is characterized by chemical properties that are most similar to both itraconazole and ketoconazole.2,5 Like other triazoles, posaconazole works by inhibiting 14 -demethylase to block the synthesis of ergosterol, which is the primary structural unit in the fungal cell membrane.9 The side chain of posaconazole is extended, and this is believed to improve binding affinity to 14 -demethylase, compared with fluconazole or other triazoles that lack this side group.7
As resistance to conventional antifungals continues to become widespread, further studies may extend posaconazole's spectrum of activity to include rare and difficult-to-treat fungal infections in patients with poor response to traditional therapy. This article will present a review of posaconazole's: 1) spectrum of activity, 2) pharmacokinetic properties, 3) clinical efficacy, and 4) comparison among other antifungal agents.
Spectrum of Activity
Posaconazole has broad-spectrum antifungal activity with demonstrated in vitro potency against yeasts and molds, including: Aspergillus spp., Zygomycetes spp., Candida spp., and several other pathogens.10,11,12 Posaconazole is also active against the less common but increasingly important emerging fungal pathogens including Scedosporium spp. and Fusarium spp.1,5In an in vitro 2-year study by Diekema et al, a total of 448 filamentous fungi isolates were tested for susceptibility to triazoles (including itraconazole, posaconazole, ravuconazole, and voriconazole) as well as to caspofungin and amphotericin B.10 The minimum inhibitory concentrations (MIC) for posaconazole, voriconazole, and amphotericin B against numerous fungal pathogens are shown in Table 1.
An additional small in vitro study highlighted posaconazole's activity against Zygomycetes (n = 37 isolates); Mucor spp, Rhizopus spp, Absidia corymbifera, Cunninghamella spp, Apophysomyces elegans, Cokeromyces recurvatus, and Saksenaea vasiformis.11 The MIC90 values (µg/mL) for posaconazole were 1, 8, 0.25, 1, 2, 4, and 0.125, respectively. In comparison to other triazoles, posaconazole had MIC means 1.6-fold lower than itraconazole, 33-fold lower than voriconazole, and 47-fold lower than fluconazole. At present, susceptibility breakpoints for antifungal agents have not been established. Moreover, since standardized methods to test the susceptibility patterns of antifungals have yet to be established, MIC values should be interpreted with caution. A case report by Ide and associates also described effectiveness in a neutropenic male patient with breakthrough Zygomycosis while on voriconazole for a past Aspergillus infection.13 The patient remained refractory to treatment with amphotericin B, but recovered successfully when switched to posaconazole 800 mg/day.
In a comparative study of in vitro activity against pathogenic yeasts, including strains of C. neoformans (n = 15), C. parapsilosis (n = 15), C. lusitaniae (n = 12), C. albicans (n = 23), C. tropicalis (n = 15), C. krusei (n = 15), and T. glabrata (n = 15), posaconazole and itraconazole displayed equivalent MIC90 to C. neoformans and C. krusei (60 ng/mL and 500 ng/mL, respectively).14 However, all other strains were more susceptible to posaconazole (2-4-fold lower MIC90 values than itraconazole) except for T. glabrata, which had a comparably high MIC90 (> 1000 ng/mL) as itraconazole (1000 ng/mL). Similarly, an in vitro study (n = 3 strains) conducted by Perfect et al showed that posaconazole killed yeasts at a lower MIC90 (0.063 µ/mL) than either fluconazole or amphotericin B (2.0 µ/mL and 1.0 µ/mL, respectively), but was inferior to itraconazole (0.008 µ/mL).15 A recent in vivo combination study of posaconazole with amphotericin B deoxycholate demonstrated additive effects of combination therapy (20.3% of 64 combinations; 4 strains) versus Candida albicans (increased survival of mice).16 In addition, no antagonism between posaconazole and amphotericin B was observed in this study.
Resistance of Fusarium spp. to several other triazoles led to an investigation of posaconazole as a treatment option for the eradication of this pathogen. A case report by Herbrecht et al showed successful treatment of F. proliferatum infection with posaconazole in a 62-year-old lung transplant patient.1 The patient was not able to take amphotericin B because of renal insufficiency and, after susceptibility testing showed poor activity of itraconazole and fluconazole, posaconazole therapy resulted in successful eradication of the pathogen.
Meletiadis and colleagues' in vitro study displayed positive results against 55 clinical isolates of S. prolificans and 13 clinical isolates of S. apiospermum.17 Although posaconazole showed efficacy against Scedosporium spp. isolates in this study (S. prolificans [MIC50 ≥ 8 µ/mL, MIC90 ≥ 8 µ/mL] and S. apiospermum [MIC50 = 0.5 µ/mL, MIC90 = 1 µ/mL]), voriconazole had lower MICs for both Scedosporium spp. isolates (S. prolificans [MIC50 = 4 µ/mL, MIC90 = 4 µ/mL] and S. apiospermum [MIC50 = 0.125 µg/mL, MIC90 = 0.25 µ/mL]). Voriconazole and other azoles, however, were also observed to exhibit cross-resistance, whereas posaconazole did not. Conversely, in an in vitro study performed by Carrillo and Guarro, posaconazole and voriconazole displayed equivalent MIC90 to S. apiospermum (11 isolates).18 The disparity in the reported activities of posaconazole and voriconazole against S. apiospermum highlights the need for further study of the efficacy of triazoles against Scedosporium spp.
Pharmacologic Properties
Posaconazole, like the other azoles in clinical use for systemic treatment (fluconazole, itraconazole, voriconazole), is available as an oral suspension. The specific doses that will be marketed if FDA approval is granted for posaconazole have not been established. Phase III clinical trials with posaconazole in patients with graft-versus-host disease (GVHD), acute myelogenous leukemia (AML), or myelodysplastic syndrome (MDS), and in hematopoietic stem cell transplant (HSCT) recipients, evaluated a daily dose of 600 mg/d, divided in 3 doses.4,12 Other clinical trials with posaconazole in patients with oropharyngeal candidiasis or refractory invasive fungal infections (IFI), evaluated daily doses of 100mg/d (200 mg loading dose), and 800 mg/d (divided in 2 or 4 doses), respectively.5,19,20,21
Posaconazole bioavailability increases with both nonfat meal and high-fat meal (2.6-fold and 4.0-fold, respectively), thereby supporting administration of this drug with food.2,22 Unlike itraconazole and ketoconazole, whose absorption is affected by gastric pH, posaconazole is not affected and has consistent absorption patterns, regardless of the intestinal environment.2 No dose adjustments are recommended for renal or hepatic insufficiency, as posaconazole is mainly excreted in the feces with minimal urinary excretion or hepatic metabolism.23.24
Posaconazole is metabolized via UDP-glucuronyl transferase (UGT) enzymes in the liver, is highly protein bound, and has a large volume of distribution, making it unnecessary to dose-adjust for patients undergoing hemodialysis.3,5 Wexler and colleagues demonstrated that posaconazole is minimally inhibited by the cytochrome P450 isoenzyme (CYP), with inhibition of hepatic CYP3A4 occurring below micromolar concentrations, and with no inhibition of isoenzymes 1A2, 2A6, 2C9, 2C19, and 2D6.3
Table 2 summarizes the mechanism of action, spectrum of activity, pharmacokinetics, dosing/ administration, adverse effects, and the drug-interaction profile of posaconazole.
Clinical Efficacy
In July 2004, Schering-Plough Pharmaceuticals submitted a New Drug Application (NDA) to the US FDA, to market posaconazole for the treatment of IFIs in patients who are intolerant of other antifungals or with refractory disease. Additionally, the NDA also seeks US marketing approval of posaconazole for prophylaxis of serious IFIs in patients who are at high risk of acquiring these infections and for oropharyngeal Candidiasis.2,25
Although Schering-Plough Pharmaceuticals submitted an NDA for posaconazole to the FDA nearly 2 years ago, the majority of the Phase III clinical trial data are yet to be published. Trials were conducted in the United States, Australia, Singapore, Europe, Canada, Latin America, and South Africa, and included over 1300 patients.4,5,12,20,21 Detailed summaries of the clinical trials evaluating the efficacy of posaconazole in patients at high risk of developing IFIs can be found in Table 3.4,12 See Table 4 in the July issue, which will outline the key data regarding the efficacy of posaconazole in patients with oropharyngeal candidiasis and in patients with zygomycosis.
Ullman and colleagues compared the efficacy of posaconazole and fluconazole against Aspergillosis and other IFIs as prophylactic treatment in high-risk HSCT (or GVHD) patients (n = 600).4 During the treatment period for patients given posaconazole and fluconazole (mean = 80.3 and 77.2 days, respectively), posaconazole resulted in lower incidences of proven/probable fungal infections for Aspergillus spp (P = 0.001) and all IFIs (P = 0.004). Similar results were shown during the primary time period (study period, 112 days) with lower incidences of Aspergillosis (P = 0.006) and all IFIs (P = 0.074) for the posaconazole-treated subjects. In addition to superiority in prevention of Aspergillosis spp and IFIs during the treatment period, posaconazole therapy prolonged the time to development of breakthrough infections compared with fluconazole therapy.
The results of another randomized, evaluator-blinded, active controlled, multi-center phase III clinical study by Cornely and colleagues support the use of posaconazole as prophylaxis to IFIs over fluconazole and itraconazole in neutropenic patients with AML or MDS undergoing myelosuppressive chemotherapy (n = 602).12 Not only did posaconazole (n = 304) show a significant advantage over standard triazoles (n = 298) in regards to lower incidences of all IFIs during the treatment period (prophylaxis meanpos = 29 days, prophylaxis meanflu/itra = 25 days; P = 0.0001), but was also superior within 100 days post-randomization (P = 0.0031).
Posaconazole has been studied in the treatment of IFIs characterized by refractoriness or intolerance to other anti-fungal agents. The results of the first Phase III trial of posaconazole were presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington DC, in September 2004.5 In this open-label study, 330 patients received 800 mg/day posaconazole suspension (divided doses) and 279 external control patients received other antifungal agents (primarily amphotericin B deoxycholate). The study population was primarily comprised of patients infected with Aspergillus (posaconazole, 45%; control, 40%). Other patients were infected with Candida (posaconazole, 10%; control, 14%), Fusarium (posaconazole, 8%; control, 2%), Cryptococcus (posaconazole, 13%; control, 29%), and Zygomycetes (posaconazole, 5%; control, 4%). Success, defined as a complete or partial response, was seen in 42% of posaconazole-group compared with 26% of control-group patients with Aspergillosis. This difference was significant in favor of posaconazole (P = 0.006). Of note, a successful outcome was reported for 3 of 6 patients with voriconazole-refractory invasive Aspergillosis.
To date, one pivotal, randomized, evaluator-blinded study has compared the efficacy of posaconazole to that of fluconazole for the treatment of oropharyngeal candidiasis.20 The primary efficacy measure used in this study was complete or partial resolution of the signs and symptoms of oropharyngeal Candidiasis. The primary end point was achieved by 91.7% and 92.5% of the posaconazole- and fluconazole-treated patients, respectively (absolute difference, -0.8%, 95% CI, -6.61% to 5.04%). In addition, sustained mycologic success at 28 days post-treatment was achieved by a greater number of posaconazole-treated patients compared with the fluconazole group (P = 0.038).
References
- Herbrecht R, et al. Successful Treatment of Fusarium proliferatum Pneumonia with Posaconazole in a Lung Transplant Recipient. J Heart Lung Transplant. 2004; 23:1451-1454.
- Courtney R, et al. Pharmacokinetics of Posaconazole Co-Administered with Antacid in Fasting and Nonfasting Healthy Men. Antimicrob Agents Chemother. 2004;48:804-808.
- Wexler D, et al. Effect of Posaconazole on Cytochrome P450 Enzymes: A Randomized, Open-Label, Two-Way Crossover Study. Eur J Phar Sci. 2004;21:645-653.
- Ullmann A, et al. Posaconazole vs Fluconazole for Prophylaxis of Invasive Fungal Infections in Allogeneic Hematopoietic Stem Cell Transplant Recipients with Graft-versus-Host Disease [Poster]. 47th ASH Annual Meeting; 2005 Dec 10-13: Atlanta, GA
- Keating GM. Adis Drug Profile: Posaconazole. Drugs. 2005;65:1553-1567.
- Courtney R, et al. Posaconazole Pharmacokinetics, Safety, and Tolerability in Subjects with Varying Degrees of Chronic Renal Disease. J Clin Pharmacol. 2005;45:185-192.
- Xiao L, et al. Three-Dimensional Models of Wild-Type and Mutated Forms of Cytochrome P450 14 -sterol Demethylases from Aspergillus fumigatus and Candida albicans Provide Insights Into Posaconazole Binding. Antimicrob Agents Chemother. 2004;48:568-574.
- Courtney R, et al. Pharmacokinetics, Safety, and Tolerability of Oral Posaconazole Administered in Single and Multiple Doses in Healthy Adults. Antimicrob Agents Chemother. 47:2788-2795.
- Munayyer HK, et al. Posaconazole is a Potent Inhibitor of Sterol 14 -Demethylation in Yeasts and Molds. Antimicrob Agents Chemother. 2004;48:3690-3696.
- Diekema D, et al. Activities of Caspofungin, Itraconazole, Posaconazole, Ravuconazole, Voriconazole, and Amphotericin B Against 448 Recent Clinical Isolates of Filamentous Fungi. J Clin Microbiol. 2003;41:3623-3626.
- Sun QN, et al. In Vitro Activities of Posaconazole, Itraconazole, Voriconazole, Amphotericin B, and Fluconazole Against 37 Clinical Isolates of Zygomycetes. Antimicrob Agents Chemother. 2002;46:1581-1582.
- Cornely OA, et al. Posaconazole vs Standard Azole (FLU/ITRA) Therapy for Prophylaxis of Invasive Fungal Infection (IFIs) Among High-Risk Neutropenic Patients: Results of a Randomized, Multicenter Trial [Poster]. 47th ASH Annual Meeting; 2005 Dec 10-13: Atlanta, GA
- Ide L, et al. Zygomycosis in Neutropenic Patients with Past Aspergillus Infection: A Role for Posaconazole? Clin Microbiol Infect. 2004;10:862-863.
- Galgiani JN, Lewis ML. In Vitro Studies of Activities of the Antifungal Triazoles SCH56592 and Itraconazole Against Candida albicans, Cryptococcus neoformans, and Other Pathogenic Yeasts. Antimicrob Agents Chemother. 1997;41:180-183.
- Perfect JR, et al. In Vitro and In Vivo Efficacies of the Azole SCH56592 Against Cryptococcus neoformans. Antimicrob Agents Chemother. 1996;40:1910-1913.
- Cacciapuoti A, et al. Interaction Between Posaconazole and Amphotericin B in Concomitant Treatment Against Candida albicans In Vivo. Antimicrob Agents Chemother. 200;49:638-642.
- Meletiadis J, et al. In Vitro Activities of New and Conventional Antifungal Agents Against Clinical Scedosporium Isolates. Antimicrob Agents Chemother. 2002;46:62-68.
- Carrillo AJ, Guarro J. In Vitro Activities of Four Novel Triazoles Against Scedosporium spp. Antimicrob Agents Chemother. 2001;45:2151-2153.
- Ullman AJ, et al. Pharmacokinetics, Safety, and Efficacy of Posaconazole in Patients with Persistent Febrile Neutropenia or Refractory Fungal Infection. Antimicrob Agents Chemother. 2006;50:658-666.
- Vazquez JA, et al. A Multicenter Randomized Trial Evaluating Posaconazole versus Fluconazole for the Treatment of Oropharyngeal Candidiasis in Subjects with HIV/AIDS. Clin Infect Dis. 2006;42:1179-1186.
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