Review: Clinical Trial Outcomes New-generation triazole antifungal drugs: review of the Phase II and III trials Clin. Invest. (2011) 1(11), 1577–1594 In this article, the pharmacological, microbiological and clinical development Corrado Girmenia†1 & Erica Finolezzi1 progress from Phase II and III clinical trials with the new generation triazoles 1Dipartimento di Ematologia, Oncologia, albaconazole, isavuconazole, posaconazole, ravuconazole and voriconazole Anatomia Patologica & Medicina Rigenerativa, are reviewed. These drugs exhibit a favorable toxicity profile and possess high Azienda Policlinico Umberto I, Via Benevento 6, 00161, Rome, Italy activity against resistant and emerging fungal pathogens. Pharmacokinetic †Author for correspondence: may be affected by variability in metabolism and/or gastrointestinal Tel.: +39 0685 7951 absorption. Only voriconazole and posaconazole have been adequately Fax: +39 0644 241 984 investigated and are now indicated in the treatment and prophylaxis of E-mail: [email protected] invasive fungal diseases. Other triazoles; albaconazole, isavuconazole and ravuconazole are under development; therefore, their future use is unknown. Keywords: albaconazole • antifungal prophylaxis • antifungal therapy • isavuconazole • Phase II and III trials • posaconazole • ravuconazole • triazoles • voriconazole Opportunistic invasive fungal diseases (IFDs) are a major cause of morbidity and mortality in immunocompromised patients, particularly those affected by hematological diseases and cancer, and those undergoing transplant procedures or prolonged immunosuppressive therapy. Considerable progress in treating systemic mycoses has been achieved in recent years through better use of old antifungal agents and through development of new drugs in association with more advanced diagnostic procedures. The search for new antifungal strategies has been mainly focused on the reduction of toxicity, enhancement of bioavailability, improvement of the antifungal spectrum and counteraction of resistance. The introduction of the first-generation triazoles; fluconazole and itraconazole, represented a major advance in the treatment of IFDs, and they have been recommended, along with amphotericin B, as a first-line prophylaxis and therapy of IFDs for several years, until the advent of the new antifungal molecules [1,2]. Both drugs continue to be widely used for the prevention and treatment of superficial and deep-seated fungal infections; however, a number of clinically important limitations were demonstrated early in relation to their spectrum of activity, the development of resistance and some toxicity. In order to overcome these limitations, several analogues have been developed. These new generation triazole antifungal drugs, the so-called second-generation triazoles, include albaconazole (Stiefel Laboratories Inc.), isavuconazole (Basilea Pharmaceutica International), posaconazole (Merk Sharp & Dohme), ravuconazole (Bristol-Myers Squibb) and voriconazole (Pfizer Pharmaceuticals). These new drugs are more active against difficult to treat and emerging pathogens compared with fluconazole and itraconazole; they have all been evaluated in in vitro preclinical and Phase I studies and some of them have been investigated in Phase II and III clinical trials. Pharmacokinetic characteristics of the new generation triazole antifungals Among second-generation triazoles, albaconazole (UR-9825), posaconazole and voriconazole are available as active drugs. Isavuconazole (BAL-4815) is the active metabolite of the water-soluble prodrug isavuconazonium (BAL-8557) [3–6]. The iv. prodrug of ravuconazole (BMS-207147) is ravuconazole di-lysine phosphoester 10.4155/CLI.11.137 © 2011 Future Science Ltd ISSN 2041-6792 1577 Review: Clinical Trial Outcomes Girmenia & Finolezzi (BMS-379224) [7–12]. The chemical structures of Reduced absorption and increased or decreased albaconazole, isavuconazonium, ravuconazole and metabolism related to genetic factors or drug voriconazole are similar to that of fluconazole, interactions may result in insufficient exposure of whereas posaconazole bears chemical resemblance to the fungal pathogen to the treatment, or excess drug itraconazole. concentrations with potential toxicity. The only tool The pharmacokinetic characteristics of the second- available to determine drug exposure to the patient generation triazoles are summarized in Table 1 [3–21]. All is monitoring of drug concentration in blood by triazoles have been synthesized as oral formulation. All therapeutic drug monitoring (TDM) [22,26–31]. Validated the triazoles except albaconazole are also available as an assays have been developed for each of the commonly iv. formulation. An iv. formulation of posaconazole has used antifungal drugs. These assays most often been more recently synthesized, and a Phase I study in include either a microbiological or chromatographic adult leukemic patients is ongoing (NCT01075984). assay, but it should be mentioned that microbiological The absorption of itraconazole capsules, posaconazole methods may give nonlinear results and are not able and ravuconazole is enhanced by co-administration to distinguish between antifungal drugs in patients on with food or nutritional supplements [8–10,14–18]. On multiple antifungals. A definitive voriconazole trough the contrary, co-administration with food decreases concentration goal is likely to be in the range of 2–6 µg/ the absorption of fluconazole, itraconazole solution ml [26–31]. The adequate serum levels of posaconazole and voriconazole. No clinically relevant food effect on have not been well defined to date; however, some isavuconazole oral absorption has been observed [19]. authors proposed a trough posaconazole goal ranging No data are available for albaconazole in humans to between 0.5 and 1.5 µg/ml for patients treated for our knowledge. IFDs and levels more than 0.5 µg/ml for prophylaxis Despite similar mechanisms of action, structural [22]. Recent literature increasingly underlines the differences of the triazoles result in distinct crucial role of adequate plasma levels of voriconazole pharmacokinetic properties including metabolism and and posaconazole in the efficacy of treatment elimination. A common characteristic of these antifungal and prevention of IFDs in immunocompromised drugs is the variability of concentration in blood among patients, respectively [22,25–33]. In particular, studies different patients and during the treatment course in in the pediatric population demonstrate that TDM the same patient. Triazoles are degraded mainly in the and individual dose adjustments are recommended liver, where they undergo glucuronidation, and their for optimal and less toxic voriconazole treatments, metabolism is greatly influenced by the activity of the especially for <3 year-old children [31,34,35]. However, hepatic enzymes. In particular, voriconazole is subject to the available, good-quality, prospectively obtained variability in blood concentrations for both iv. and p.o. data in the therapeutic and prophylactic setting are formulations. This variability is not related primarily insufficient to justify the routine use of TDM in patients to absorption, unlike itraconazole and posaconazole under treatment with voriconazole and posaconazole. [20–22]. Some studies demonstrated that most of the In general, the assay should be considered for both pharmacokinetic variability of voriconazole is due to the voriconazole and posaconazole in the event of poor ability to metabolize the drug via the CYP2C19 P450 clinical response, co-administration of potentially enzyme [20,22]. Polymorphism in the gene encoding interacting drugs and deteriorating hepatic function. this enzyme is common and results in variable rates of For voriconazole, TDM may be indicated in suspected voriconazole metabolism. These polymorphisms differ neurologic toxicity related to overdosing. A specific among the various ethnic groups, in fact most Caucasians indication for monitoring posaconazole levels is the are homozygous extensive metabolizers and Asians occurrence of conditions that put the patient at risk are more frequently homozygous poor metabolizers. of impaired absorption, such as severe mucositis, The genetic variability of CYP2C19 represents an vomiting, diarrhea, intestinal graft-versus-host important issue in the definition of proper dosages and disease, and impaired dietary intake. However, only response to treatment of voriconazole. For posaconazole, a few centers have a clinical pharmacology laboratory pharmacokinetic investigation has identified marked capable of routinely performing TDM of the triazoles. interpatient variability related to the erratic absorption An increase in the number of such laboratories should of the oral drug more than to the variable metabolism be encouraged in order to gather more data and better considering that posaconazole metabolism is related define the indications of TDM of these antifungal only to CYP3A4 [23–25]. Additionally, the more recently drugs in clinical practice. developed triazoles; albaconazole, isavuconazole and Patients with impaired renal function can be ravuconazole are metabolized via the P450 enzymes treated with the standard dosage of oral voriconazole. although there is little information available to date. iv. voriconazole is not indicated in this setting due to 1578 www.future-science.com future science group New-generation triazole antifungal drugs: review of the Phase II & III trials Review: Clinical Trial Outcomes e) bl% Albaconazole Oral only 2–4 Not applicable in humans (only oral formulation availaIn animals 80–100 No data 98 Very large No data No data No data 15 in rabbit model No data Hepatic enzymes (few data) 30–56 Fecal No data No data Ravuconazole Oral and intravenous 4 48–74% in animals Increased 98 10.8 0.8–1.7 (doses ranging from 400 to 800 mg given orally) Achieved after 29 days 6 mg/l (400 mg/24 h) 10 in rabbit model 15 in rabbit model Only by CYP3A4 hepatic enzyme 76–202 Fecal No data No dose adjustment needed for both renal and hepatic dysfunction al n s. Isavuconazole Oral and intravenous 2–3 Very high No effect 98 4.4–7.7 2.5 (dose 100 mg) Achieved after 7–10 days 2 mg/l (100 mg/24 h) Low in CSF, higher in brain Low Hepatic enzymes (few data) 56–104 Fecal 1< Administration to patients with mild or moderate hepatic impairment requires a dose adjustment compared with normal patients. No dose adjustment needed for both reand hepatic dysfunction e ond-generation triazol Posaconazole Oral only 5 Not applicable in humans (only oral formulation available) In animals 52–100% Increased, particularly by fatty meals 99 6.5 0.6 (after a single dose of 400 mg); 1.3 ( after 200 mg tid) Achieved after 7–10 days 1 mg/l (400 mg/12 h) Low 26 Only by CYP3A4 hepatic enzyme 16–35 Fecal 2< Not dose adjustment needed for both renal and hepatic dysfunction tic properties of the sec Voriconazole Oral and intravenous 2 95% Decreased 58 4.6 3 (dose 3 mg/kg b.i.d. intravenously); 1.89 (dose 200 mg b.i.d. given orally) Achieved after 5–6 days 5 mg/l (4 mg/kg/12 h) 50> 38 Various hepatic enzymes (CYP3A4, CYP2C19, CYP2C8/9) 6–12 Renal 2< Need to adjust dose in hepatic dysfunction; intravenous formulation is contraindicatedin patients with creatinine clearancerates 50 ml/min< e Table 1. Summary of pharmacokin Pharmacokinetic property Available forms Absorption rate: time of maximum plasma concentrations after oral administration (h) Bioavailability. Expressed as ratio of serum level after oral route to those after intravenous route Food effect on absorption Protein binding (%) Volume of distribution (l/kg) Maximum plasma concentrations (mg/l) Steady state following oral administration Serum levels at the steady state considering the through plasma concentrations (dosage) CNS/CSF penetration (% of serum levels) Vitreal penetration (% of serum levels) Metabolism Half-life (h) Route of elimination Urinary elimination in active form (%) Dose adjustment future science group Clin. Invest. (2011) 1(11) 1579 Review: Clinical Trial Outcomes Girmenia & Finolezzi the solvent cyclodextrin accumulates, although its studies show that the pan-azole cross resistance pattern potential nephrotoxicity is uncertain. In patients with in A. fumigatus strains may develop through exposure moderate hepatic failure (Child–Pugh A and B stage) the to azole compounds in the environment [43]. voriconazole clearance has been found to be reduced by Currently, there are two independent standards for approximately 50%; therefore, a 50% reduction of the antifungal susceptibility testing of triazoles against maintenance dose is required. For patients with advanced fungi: the broth microdilution method, developed by the liver cirrhosis (Child–Pugh C stage) pharmacokinetic Clinical and Laboratory Standards Institute and that of data are lacking and the administration of the drug is the European Committee on Antimicrobial Susceptibility not indicated [36]. Renal clearance of posaconazole is Testing. To define the susceptibility pattern of fungi negligible; therefore, in patients with renal impairment the two methods differently determined the clinical as well as in patients on intermittent hemodialysis, no breakpoints (CBT) based upon the correlation of in vitro significant alteration in posaconazole pharmacokinetic data with clinical outcome and the epidemiological cut-off was observed and no dose adjustment is required [37]. values (ECV) that would discriminate wild type strains Administration of isavuconazole to patients with mild from those with acquired resistance mechanisms. The or moderate hepatic impairment will require a dose CBT is used to predict the response to treatment based adjustment compared with normal patients [38]. on the level of susceptibility of the pathogen, whereas the ECV could serve as the foundation for the laboratory Antimicrobial characteristics of the detection of acquired resistance and be used to monitor new-generation triazole antifungals resistance development. As detailed in Table 2, both CBT The phenomenon of resistance to triazoles has been and ECV are available for Candida spp, whereas, in the largely described for fluconazole and itraconazole absence of the necessary clinical data, CBTs have not and it continues to be an important issue for second- been established for any Aspergillus/drug combination generation triazoles. While clinically relevant data and only ECVs have been defined [44–47]. are available for Candida resistance to triazole, the Isavuconazole, ravuconazole and albaconazole epidemiological and clinical impact of triazole resistance have not been assigned an interpretive breakpoint; among moulds is less known. Azole antimycotics block however, for purpose of comparison and based on the conversion of lanosterol to ergosterol through the pharmacokinetic data, some authors employed the inhibition of C14-a demethylase. C14-a demetilase susceptibility/resistance breakpoints of voriconazole is the product of the ERG11 gene present in practically also for these drugs. Table 3 details the distribution all yeasts and moulds. A low activity of triazoles of the minimal inhibitory concentrations required against Candida spp can occur by mutations of the to inhibit the growth of 90% of treated organisms ERG11 gene that modify the demethylase, resulting (MIC ) of fluconazole, itraconazole, voriconazole, 90 in a reduced affinity of azoles to the target molecule, posaconazole, ravuconazole, isavuconazole and or by the overexpression of the ERG11 gene resulting albaconazole against Candida spp and Cryptococcus  in an overproduction of the demethylase. Another neoformans isolates from large international studies [48– important resistance mechanism is the overexpression 64]. Second-generation triazoles demonstrated potent of the efflux pump genes encoded by the CDR genes in vitro activity against all species of Candida and of the ATP-binding cassette and major facilitator C. neoformans. In particular albaconazole showed the class. The resistance mechanism related to mutation lowest MIC for all Candida spp. One factor behind 90 or overexpression of target molecule impairs drug the development of second-generation triazoles was the binding, whereas overexpression of the efflux pump rapid appearance of fluconazole-resistant organisms decreases intracellular drug concentration [39,40]. during long-term treatment. Generally, all these drugs The phenomenon of resistance to the new triazoles has are more active than fluconazole and itraconazole been recently observed for Aspergillus spp. The emergence against a wide variety of Candida spp, such as C.  of triazole resistance in Aspergillus isolates, particularly albicans, C. parapsilosis, C. tropicalis and C. krusei, A. fumigatus, has been reported in several countries whereas their activity continues to be moderate against and some studies seem to show that this phenomenon a significant proportion of C.glabrata isolates (Table 4). might have a significant impact on the role of azoles An important characteristic of the second- in the management of invasive aspergillosis (IA) [39,41]. generation triazoles is their activity potentially Several mechanisms of resistance to azoles have been extended not only to Aspergillus spp but also to other described for Aspergillus spp: point mutations of Cyp51A less common filamentous fungi such as zygomycetes, (gene encoding 14-a-sterol demethylase) with reduced Fusarium spp and Scedosporium spp [65–76]. To date no concentration of intracellular drug, over expression of interpretive breakpoint for susceptibility of moulds efflux pumps or reduced drug penetration [39–42]. Recent to antifungal drugs has been standardized; however, 1580 www.future-science.com future science group New-generation triazole antifungal drugs: review of the Phase II & III trials Review: Clinical Trial Outcomes Table 2. Susceptibility breakpoints according to the Clinical and laboratory standards institute and European committee on antimicrobial susceptibility testing for Candida and Aspergillus species. Pathogen Clinical breakpoints (mg/l) Epidemiological cut-off value (mg/l) CLSI EUCAST CLSI EUCAST Candida Fluconazole ≤8† ≤2‡ ≤0.5–≤64§ ≤1–<128¶ Itraconazole ≤0.125† NA NA NA Voriconazole ≤1 NA ≤0.03–≤0.5# ≤0.06–≤1†† Posaconazole NA NA ≤0.06–≤2‡‡ NA Aspergillus Itraconazole NA NA ≤1–≤2§§ ≤1 Voriconazole NA NA ≤1–≤2¶¶ ≤1 Ravuconazole NA NA NA ≤1 Posaconazole NA NA ≤0.25–≤1## ≤0.25 †Applied to all species of Candida except for C. krusei. ‡Applied to C. albicans, C. parapsilosis and C. tropicalis. §≤0.5 for C. albicans; ≤2 for C. parapsilosis, C. tropicalis and C. lusitaniae; ≤8 for C. guilliermondii; ≤32 for C. glabrata and ≤64 for C. krusei. ¶≤1 for C. albicans; ≤2 for C. parapsilosis and C. tropicalis; ≤32 for C. glabrata and ≤128 for C. krusei. #≤0.03 for C. albicans and C. lusitaniae; ≤0.06 for C. tropicalis; ≤0.125 for C. parapsilosis; ≤0.25 for C. guilliermondii and ≤0.5 for C. glabrata and C. krusei. ††≤0.06 for C. lusitaniae; ≤0.125 for C. albicans, C. parapsilosis, C. tropicalis and C. paratropicalis; ≤0.25 for C. parapsilosis; ≤5 for C. guilliermondii and C. krusei and ≤2 for C. glabrata. ‡‡≤0.06 for C. albicans; ≤0.125 for C. tropicalis and C. lusitaniae; ≤0.25 for C. guilliermondii and ≤1 for C. glabrata and C. krusei. §§≤1 for A. fumigatus, A. flavus, A. terreus and A. nidulans and ≤2 for A. niger and A. versicolor. ¶¶≤1 for A. fumigatus, A. flavus and A. terreus, and ≤2 for A. niger, A. nidulans and A. versicolor. ##≤0.25 for A. flavus; ≤0.5 for A. fumigatus, A. niger and A. terreus and ≤1 for A. nidulans and A. versicolor. CLSI: Clinical and laboratory standards institute; EUCAST: European committee on antimicrobial susceptibility testing; NA: Not available. Data taken from [43–46,201]. some authors considered a MIC >2 µg/ml as the of azole resistance in Aspergillus spp in some European provisional resistance breakpoint for itraconazole, countries, although azole resistance prevalence voriconazole and posaconazole [65]. The definition of in Aspergillus spp seems uncommon according to these breakpoints is not based on careful correlations multinational studies [38–42,69]. An in vitro survey of in vitro with in vivo response to therapy, even of triazole cross-resistance performed among more though itraconazole and voriconazole clinical failures than 700 clinical isolates of Aspergillus spp, collected in aspergillosis have been correlated with MICs >2 from 2000 to 2006 as part of a global antifungal µg/ml. We can hypothesize that this resistance surveillance program, showed a pattern of resistance breakpoint may be extended to all broad spectrum (MIC >2 µg/ml) for itraconazole in approximately triazoles including ravuconazole, isavuconazole 2% of isolates, and in less than 1% of the isolates for and albaconazole. Table 5 details the distribution of voriconazole, posaconazole or ravuconazole [69]. MIC of itraconazole, voriconazole, posaconazole, 90 ravuconazole, isavuconazole and albaconazole Phase II & III clinical trials against Aspergillus spp and other filamentous fungi ■ Voriconazole from large international studies [52,53,64,66,67,69,71–76]. Clinical trials of voriconazole antifungal therapy All second-generation triazoles are highly active Voriconazole has been evaluated in large comparative against Aspergillus spp including A. terreus and A.  trials in the empiric antifungal therapy of febrile flavus, which may have an intrinsically reduced neutropenia, the treatment of superficial and deep-seated susceptibility to amphotericin B. Posaconazole is the candidiasis, the primary therapy of IA and the treatment only triazole active against all species of zygomycetes, of ocular fungal infections [77–82]. Noncomparative and itraconazole showed in vitro activity against all studies on infections caused by rare fungal pathogens, zygomycetes except Mucor spp. As previously observed, such as Fusarium spp and Scedosporium spp evaluated recent literature underlines the emerging phenomenon the therapeutic role of voriconazole [83,84]. future science group Clin. Invest. (2011) 1(11) 1581 Review: Clinical Trial Outcomes Girmenia & Finolezzi Table 3. In vitro activities of first- and second-generation triazoles against Candida spp and Cryptococcus neoformans. Species, reference Range of MIC † 90 (no. of isolates) Fluconazole Itraconazole Voriconazole Posaconazole Ravuconazole Isavuconazole Albaconazole C. albicans 0.5–4 0.12–0.25 0.015–0.25 0.06 0.03–0.25 <0.015 <0.0002 C. glabrata 16–64 1–2 1–2 2 1–2 0.5 0.12 C. krusei 64–128 0.25–2 0.5 1 0.5 0.5 0.06 C. parapsilosis 1–2 0.06–0.5 0.06–0.12 0.12 0.06–0.12 0.03 ≤0.0002 C. tropicalis 1–8 0.03–0.5 0.06–0.12 0.12 0.12 0.06 0.03 C. guilliermondii 4–16 1 0.12–0.25 0.5 0.25 N/A N/A C. dubliniensis 0.25–16 0.25 0.03 0.06 0.03–1 N/A N/A C. neoformans 4–32 0.25–0.5 0.125–0.5 0.016–0.5 0.25–0.5 0.016–0.06 0.156 †The MIC end point was defined as the lowest concentration that produced 50% inhibition of growth. MIC: Minimal inhibitory concentration. Data taken from [48–53,55–58,60–62]. Empirical antifungal therapy receiving voriconazole suffered from more episodes In a randomized, international, multicenter of transient visual disturbances than those receiving trial, voriconazole was compared with liposomal liposomal amphotericin B (22 vs 1%; p < 0.001) and amphotericin B for empirical antifungal therapy of more hallucinations (4.3 vs 0.5%; p < 0.001). Based on neutropenic patients with persistent fever [77]. the results of this study, voriconazole did not receive the The aim of the study was to demonstrate approval for empiric antifungal therapy in patients with noninferiority of voriconazole predefined as a febrile neutropenia by regulatory agencies. difference in success rates (considering a composite end point) between the two drugs of no more than 10 Invasive candidiasis percentage points. A total of 415 patients were assigned The efficacy, safety, and tolerability of voriconazole and to voriconazole and 422 to liposomal amphotericin B. fluconazole were compared in 391 immunocompromised The overall success rates were 26.0% with voriconazole patients with mycology- and biopsy-proven esophageal and 30.6% with liposomal amphotericin B (95% CI candidiasis [78]. Primary efficacy ana lysis (256 patients) for the difference, -10.6 to 1.6%). According to this of esophageal treatment, as assessed by esophagoscopy, result voriconazole did not reach the end point of non- revealed success rates of 98.3% with voriconazole inferiority, compared with liposomal amphotericin B. and 95.1% with fluconazole. The overall safety and However, patients treated with voriconazole experienced tolerability of both antifungals were acceptable. The fewer breakthrough IFDs (1.9 vs 5.0%; p = 0.02), fewer most frequent adverse events (23%) with voriconazole cases of severe infusion-related reactions (p < 0.01) were mild, transient visual disturbances. and of nephrotoxicity (p < 0.001) than those treated A multicenter, randomized, noninferiority with liposomal amphotericin B. The incidence of study compared voriconazole (283 patients) with a hepatotoxicity was similar in the two groups. Patients regimen of amphotericin B followed by fluconazole Table 4. In vitro activities of itraconazole and second-generation triazoles against Candida spp isolates resistant to fluconazole. Species, reference MIC (% susceptible according to CLSI clinical breakpoints)† 90 (no. of isolates) Itraconazole Voriconazole Posaconazole Ravuconazole Isavuconazole‡ Albaconazole‡ C. albicans >8 (0) >8 (57) 1 (98) >8 (73) 1 0.03 C. glabrata >8 (0) 8 (13) >8 (5) 8 (11) 1 1 C. krusei 1 (2) 1 (98) 1 (98) 1 (98) 0.06 0.06 †The MIC end point was defined as the lowest concentration that produced 50% inhibition of growth. ‡ The few data available for isavuconazole and albaconazole do not allow to calculate the percentage of susceptibility. MIC: Minimal inhibitory concentrations. Data taken from [48,55,57,63,64]. 1582 www.future-science.com future science group New-generation triazole antifungal drugs: review of the Phase II & III trials Review: Clinical Trial Outcomes Table 5. In vitro activities of first- and second-generation triazoles against Aspergillus spp and other moulds. Species Range of MIC † 90 Itraconazole Voriconazole Posaconazole Ravuconazole Isavuconazole Albaconazole A. fumigatus 0.5–>8 0.5–1 0.5 0.5 1–2 0.125 A. flavus 0.25–1 0.5–1 0.5 1 1–2 0.25 A. niger 0.5–>8 0.5–2 0.5–1 2–4 2–4 0.5 A. terreus 0.25–0.5 0.5–2 0.25 0.5 0.5–2 N/A Mucor spp >16 >16 2 8 16 N/A Rhyzopus spp 4 >16 1 8 16 N/A Absidia spp 1 >16 0.25 N/A N/A N/A Cunninghamella spp 4 >8 1 N/A N/A N/A S. apiospermum 1–>16 0.25–1 0.25–1 0.12 N/A 1 S. prolificans >16 4–>16 16 16 N/A 2 Fusarium spp 16 4–16 16 8–16 >16 >16 Penicillium spp 2 1 1 1 N/A N/A †In most of studies the MIC end point was defined as the lowest concentration that produced complete inhibition of growth, but in some studies a 50% inhibition of growth was considered. MIC: Minimal inhibitory concentrations. Data taken from [52,53,64,66,67,69,71–76]. (139 patients) for the treatment of candidemia in received voriconazole or deoxycholate amphotericin B, non-neutropenic patients [79]. Voriconazole was non- respectively [81]. Most of the patients were affected inferior to amphotericin B/fluconazole in the primary by acute leukemia, or other hematologic diseases efficacy ana lysis, with successful outcomes in 41% undergoing intensive chemotherapy or allogeneic of patients in both treatment groups. At the last hematopoietic-cell transplantation (HSCT). At evaluable assessment, outcome was successful in 65% week 12, response was observed in 52.8% of the patients of patients assigned to voriconazole and in 71% of those in the voriconazole group (complete responses in 20.8% assigned to amphotericin B/fluconazole (p = 0.25). In and partial responses in 31.9%) and 31.6% of those the voriconazole group, treatment discontinuation in the amphotericin B group (complete responses in due to all-cause adverse events was more frequent, 16.5% and partial responses in 15.0%). The survival but serious adverse events and cases of renal toxicity rate at 12 weeks was 70.8% in the voriconazole group were significantly fewer than in the amphotericin B/ and 57.9% in the amphotericin B group. Voriconazole- fluconazole group. treated patients had significantly fewer severe drug- related adverse events, but transient visual disturbances IA were common with voriconazole (occurring in 44.8% Voriconazole has become the drug of choice for the of patients). treatment of IA. The change from amphotericin B to voriconazole for primary therapy of aspergillosis followed Fungal keratitis the publication of an open noncomparative multicenter Voriconazole was compared with natamycin as a topical study and a Phase III large multinational randomized treatment in a multicenter, double-masked, clinical trial trial [80,81]. In the first study, 141 immunocompromised that included 120 patients with fungal keratitis [82]. patients with IA were enrolled to be treated with The primary outcome was best spectacle-corrected iv. voriconazole 6 mg/kg b.i.d. iv. twice and then visual acuity (BSCVA) at 3 months. Other outcomes 3 mg/kg b.i.d. for 6–27 days, followed by 200 mg included scar size, perforations and a subana lysis of b.i.d. p.o. for up to 24 weeks [80]. Out of 116 assessable BSCVA at 3 months in patients with an enrollment patients, complete or partial responses were seen in visual acuity of 20/40 to 20/400. Compared with those 48% of cases. Good responses were seen in 60% of who received natamycin, voriconazole-treated patients those with pulmonary or tracheobronchial IA, 16% had an approximately 1-line improvement in BSCVA with cerebral IA, 58% with hematologic disorders and at 3 months in a multivariate regression model, but the 26% of allogeneic stem cell transplant recipients. In the difference was not statistically significant (p = 0.29). second study a total of 144 and 133 patients randomly Scar size and corneal perforations at 3 months was not future science group Clin. Invest. (2011) 1(11) 1583 Review: Clinical Trial Outcomes Girmenia & Finolezzi significantly different in the two treatment groups. patients. The primary end point was freedom from Patients with baseline BSCVA of 20/40 to 20/400 IFD or death, fungal-free survival at 180 days. demonstrated a trend toward a 2-line improvement in Despite trends to fewer IFDs (7.3 vs 11.2%; p = 0.12), visual acuity with voriconazole (p = 0.07). Aspergillus infections (9 vs 17; p = 0.09), and less frequent empiric antifungal therapy (24.1 vs 30.2%; Invasive fusariosis p = 0.11) with voriconazole, fungal-free survival rates The spectrum of antifungal activity of voriconazole (75 vs 78%; p = 0.49) at 180 days were similar with includes Fusarium spp and its efficacy in the treatment fluconazole and voriconazole, respectively. Relapse-free of this frequently fatal infection has been evaluated and overall survival and the incidence of severe adverse in retrospective studies [83,84]. In a recently published events were also similar. This study demonstrates international retrospective ana lysis of 73 cases of invasive comparable efficacy of fluconazole or voriconazole fusariosis, treated with voriconazole the 90 day survival prophylaxis in allogeneic stem cell transplant patients; was 42% [84]. The outcome differed according to site of however, a careful interpretation of the results is infection, underlying condition and Fusarium species. required. The study population considered in this trial The authors conclude that voriconazole is a therapeutic was at low risk of IFD. Indeed, approximately 90% of option for invasive fusariosis. patients had a standard disease risk status, over half of The Phase II and III clinical trials of therapy with transplants were matched related, the HLA match was voriconazole conducted in the last decade allowed to 6/6 in 96% of cases, half of patients did not develop be defined the position of the triazole in the treatment acute or chronic graft-versus-host disease (GVHD) armamentarium of severe invasive mycoses, and and the incidence of disease relapse/progression was highlighted by the international guidelines [85–87]. only approximately 10%. One would be interested to Available literature data strongly support the primary evaluate voriconazole’s performance in a higher risk role of voriconazole in the front-line therapy of IA, on population. This consideration is even more valid the contrary, its use in the management of invasive when looking at the results among patients with acute candidiasis is questionable compared with other myeloid leukemia, a population at higher risk for IFD antifungal drugs, such as echinocandins and lipid and with a poorer fungal-free survival. Interestingly, in formulations of amphotericin B, due to the possible this patient population voriconazole reduced IFDs (8.5 reduced activity against certain Candida isolates. vs 21%; p = 0.04) and improved fungal-free-survival Voriconazole may be used in the treatment of some (78% vs 61%; p = 0.04) compared with fluconazole [91]. severe, unusual fungal infections, such as fusariosis; The second study of primary prophylaxis compared however, it has not been compared with other antifungal voriconazole (200 mg b.i.d.) versus itraconazole drugs, such as lipid formulations of amphotericin B; (200 mg b.i.d.) in 489 patients receiving allogeneic therefore, the indication of voriconazole as a first choice HSCT for at least 100 days, and up to 180 days from treatment of such infections has not been established. conditioning [89]. The primary objective was assessed on a composite end point, including survival at 180 days ■ Clinical trials of voriconazole after transplant and no proven or probable breakthrough antifungal prophylaxis IFD and no discontinuation of the study drug for more Two controlled studies of primary prophylaxis and one than 14 days during the 100 day prophylactic period. noncomparative study of secondary prophylaxis of IFDs The voriconazole arm met the criteria for superiority with voriconazole have been conducted in allogeneic in the primary end point when compared with the stem cell transplant patients [88–90]. itraconazole arm (49.1 vs 34.5%; p = 0.0004). The median duration of voriconazole prophylaxis was longer Primary prophylaxis (97 days) than that of itraconazole (68 days), probably In the first study of primary prophylaxis, conducted due to significantly more gastrointestinal adverse events in 35 centers participating in the Bone and Marrow (nausea, vomiting and diarrhea) in the itraconazole Transplant Clinical Trials Network, voriconazole group. However, the main concern with this study was was compared with fluconazole (295 vs 305 patients) the low rate of proven or probable IFDs (three in the in a randomized, double-blind trial [88]. This study voriconazole arm and six in the itraconazole arm) and was characterized by a predefined, structured fungal the fact that superiority of voriconazole was related to screening program based on serum galactomannan the tolerability more than to the efficacy. detection triggering mandatory evaluation of IFD. Overall, the two clinical trials demonstrated Patients undergoing myeloablative allogeneic HSCT an uncertain role of voriconazole in the primary were randomized before transplant to receive study antifungal prophylaxis of patients at high risk for IFDs, drugs for 100 days, or for 180 days in higher risk although the ECIL guidelines, pending the publication 1584 www.future-science.com future science group New-generation triazole antifungal drugs: review of the Phase II & III trials Review: Clinical Trial Outcomes of the full papers, provisionally graded voriconazole aspergillosis, treatment of Candida infections, timing as AI drug in the primary antifungal prophylaxis of of empirical antifungal therapy in neutropenic patients, allogeneic HSCT patients [87]. As commented above, pharmacologic optimization, pharmacokinetics and the design of the studies may have had a role in the safety in children, adolescents and in obese subjects, uncertain results. comparison with other antifungal drugs in the treatment and prevention of fungal infections, kinetics Secondary prophylaxis of 1,3 b-d-glucan assay in patients with hematologic Voriconazole (4 mg/kg/12 h iv. or 200 mg/12 h p.o.) was malignancies receiving voriconazole (NCT00001940, evaluated in a prospective, open-label, multicenter trial NCT00059878, NCT00075803, NCT00174473, as a secondary antifungal prophylaxis in 45 allogeneic NCT00150319, NCT00150345, NCT00159822, HSCT recipients with previous proven or probable IFD NCT00289991, NCT00418951, NCT00556998, [90]. Previous IFD was a proven or probable IA in most NCT00739934, NCT00893555, NCT00836875, cases (n = 31). The primary end point of the study NCT00904995, NCT01030653, NCT01092832 and was the incidence of proven or probable recurrance NCT01207128). of new IFD after transplant. The median duration of voriconazole prophylaxis was 94 days. Eleven patients Posaconazole (24%) died within 12 months of transplantation, ■ Clinical trials of posaconazole antifungal therapy but only one due to an IFD. The 1 year cumulative Clinical trials with posaconazole investigated the incidence of IFD was 6.7 ± 3.6%. Two relapses of safety and efficacy of the triazole in the treatment infection (one candidemia and one fatal scedosporiosis) of oropharyngeal candidiasis (OPC), esophageal and one new breakthrough zygomycosis in a patient candidiasis, and salvage therapy of IFDs refractory with a previous IA occurred post-transplantation. to previous antifungal treatments. No trial has been None of the 31 patients with a previous proven or conducted in the primary therapy of IFDs. probable IA experienced recurrence of their infection. Voriconazole was discontinued in only two patients Oropharyngeal & esophageal candidiasis owing to treatment-related hepatotoxicity. This is the The clinical efficacy of posaconazole and fluconazole first prospective evidence of the efficacy and safety in the treatment of OPC in HIV-infected patients of secondary antifungal prophylaxis in protecting was compared in a randomized, controlled, evaluator- allogeneic HSCT recipients from recurring IFD. blinded study [95]. Patients received either posaconazole However, it should be considering that most patients 200 mg (178 cases) or fluconazole 200 mg (172 cases) in this series were in complete clinical and radiological oral suspension on day 1, followed by 100 mg/day of remission of their IFD at the time of transplant, which the same drug for the next 13 days. The rate of clinical may itself be an important determinant of the favorable success at the 14 day primary end point was similar outcomes observed in this high risk patient population. in the posaconazole and fluconazole arms (91.7 and Conversely, the role of voriconazole, and of other 92.5%, respectively; 95% CI; -6.61–5.04). Additionally, antifungal drugs, in the control of infection reactivation mycologic success was comparable at this time point in patients with a residual or active IFD at the time of (68% in both arms). However, at day 42 follow-up, transplant deserves further investigation [92]. fewer relapses and greated mycologic success occurred An important problem raised by some authors after the in the posaconazole arm compared with fluconazole arm first clinical experiences of voriconazole treatment was (40.6 vs 26.4%; p = 0.038). represented by the emergence of breakthrough infections A multicenter, Phase III, open-label study investigated by zygomycetes, fungi intrinsically not susceptible to the use of posaconazole in 199 HIV-infected patients the drug [93,94]. However, it was unclear if this was a with either OPC or esophageal candidiasis refractory casual phenomenon related to local epidemiology or if to previous fluconazole of itraconazole therapy [96]. the use of voriconazole represented an independent risk Clinical and mycological responses were obtained in factor for the development of such severe infections. 75.0 and 36.5% of patients, respectively. In particular, The multicenter, prospective studies of voriconazole clinical responses occurred in 73% of subjects with primary and secondary prophylaxis did not show any isolates resistant to fluconazole, 74% of subjects with increased incidence of zygomycoses, despite prolonged isolates resistant to itraconazole and 74% of subjects administration of the drug in high risk patients. with isolates resistant to both. Out of 132 clinical responders, 80 patients were assessed at a 4-week Ongoing clinical trials with voriconazole follow-up. The overall clinical relapse rate in these Voriconazole is under investigation in the following subjects was 74%. Eight subjects (4%) discontinued Phase II and III clinical trials: association therapy for therapy as a result of a treatment-related adverse event. future science group Clin. Invest. (2011) 1(11) 1585 Review: Clinical Trial Outcomes Girmenia & Finolezzi IA (400 mg/day) or itraconazole (200 mg/b.i.d.) for the Posaconazole was used as salvage therapy in patients prophylaxis of IFDs in 602 patients (aged >13 years) with IA or other mycoses refractory or intolerant to at high risk for neutropenia after receiving standard conventional antifungals [97–100]. In a post hoc ana lysis, induction chemotherapy for a new diagnosis or first 107 patients with IA treated with posaconazole (800 mg/ relapse of acute myelogenous leukemia or myelodysplastic day in divided doses) and 86 retrospective controls were syndrome [101]. Study drugs were administered at the compared [97]. Controls received the best available start of each cycle of chemotherapy and were continued standard of care for salvage therapy, in accordance for a maximum of 12 weeks (84 days) or until recovery with the clinical practice at each center (mainly from neutropenia and complete remission, or occurrence amphotericin B, but also itraconazole voriconazole, of an IFD or adverse reaction to the study drug. The echinocandins or a combination of drugs). Conventional primary efficacy end point was an intent-to-treat ana- or lipid formulation of amphotericin B and itraconazole lysis of treatment failure, defined as the occurrence of were the drugs mainly used in the prior antifungal therapy proven or probable IFDs from randomization to the end in both groups. The median duration of posaconazole of the oral treatment phase (last dose of study drug plus therapy was 56 days; the control group received salvage 7 days). Secondary end points included the incidence therapy for a median of 22 days. The overall success of IA during the oral treatment phase and at 100 days rate was 42% for posaconazole recipients and 26% for after the end of the randomization period, death from control subjects (odds ratio: 4.06; 95% CI: 1.50–11.04; any cause and time to death. Significantly fewer patients p = 0.006). The response to posaconazole was greater in in the posaconazole arm compared with the fluconazole/ patients with extrapulmonary rather than pulmonary itraconazole arm developed an IFD during the oral aspergillosis (53 vs 39% responders, respectively). treatment phase (>2 vs >8%, respectively; absolute reduction in the posaconazole group, -6% [95% CI: -9.7 Zygomycosis & fusariosis to -2.5]; p = 0.001). Although there was only a minor Other retrospective studies evaluated the efficacy difference in the frequency of infections caused by of posaconazole as a salvage therapy of invasive Candida spp between groups during the oral treatment fusariosis and zygomycosis [98–100]. In a study phase, significantly fewer patients in the posaconazole including 91 patients with invasive zygomycosis who group had IA (2 [1%] vs 20 [7%]; p < 0.001). had infection that was refractory to prior antifungal Survival was significantly longer among recipients of treatment (n = 81) or were intolerant of such treatment posaconazole than among recipients of fluconazole or (n = 10) the rate of success at 12 weeks after treatment itraconazole (p = 0.04). Serious adverse events possibly, initiation was 60%, and 21% of patients had stable or probably, related to treatment were reported in 6 and disease [98]. The overall high success and survival rates 2% of patients in the posaconazole and fluconazole or in this experience provide encouraging data regarding itraconazole group, respectively (p = 0.01). posaconazole as an alternative therapy for zygomycosis. The second study was a randomized, double-blind, A retrospective ana lysis of 21 patients with invasive multicenter trial in which posaconazole was compared fusariosis from three open-label clinical trials who had with fluconazole (400 mg/day) for the prophylaxis of disease refractory, to or who were intolerant of standard IFDs in 600 allogeneic HSCT recipients (aged >13 years) antifungal therapy, showed a successful outcome with GVHD on high-dose immunosuppressive in 48% of cases. For patients who recovered from therapy [102]. Treatment was continued for 112 days or myelosuppression, the success rate was 67%, compared until the occurrence of a proven or probable IFD. The with 20% for those with persistent neutropenia [100]. primary efficacy end point was the incidence of proven or Taken together, these data indicate the efficacy of probable IFDs during the period from randomization to posaconazole as salvage therapy for infections with a day 112. Other end points were the incidence of proven variety of different fungal pathogens. The role of this or probable IA during the treatment period, the incidence agent in primary therapy remains to be defined. of breakthrough proven or probable IFDs while patients were receiving study medications (exposure period), the ■ Clinical trials of posaconazole time to the occurrence of an IFD, the overall mortality antifungal prophylaxis in the intention-to-treat population, and mortality Two Phase III clinical studies indicated that posaconazole attributable to fungal infection in the intention-to-treat at a dose of 200 mg p.o. t.i.d. was at least noninferior to population. Discontinuation of study drug for >5 days a standard-of-care azole antifungal agent for preventing was considered treatment failure for the purposes of the IFDs in leukemia and HSCT patients [101,102]. The intent-to-treat ana lysis at the 112 days end point. The first study was a multicenter, randomized, open-label mean duration of posaconazole and fluconazole therapy trial that compared posaconazole with fluconazole was 80 days and 77 days, respectively. At the end of the 1586 www.future-science.com future science group