Voriconazole—A New Therapeutic Agent with an Extended Spectrum of Antifungal Activity J

View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Elsevier - Publisher Connector

Voriconazole—a new therapeutic agent with an extended spectrum of antifungal activity J. P. Donnelly1 and B. E. De Pauw2

1Department of Haematology and 2Department of Blood Transfusion and Transplant Immunology, University Medical Center St Radboud, Nijmegen, the Netherlands

ABSTRACT Voriconazole is a new antifungal agent that can be given orally and intravenously. It has proven efﬁcacy for treating candidosis and invasive aspergillosis as well as other mould infections, such as those caused by Fusarium and Scedosporium spp. The drug is generally well tolerated. Keywords Voriconazole, antifungal treatment, invasive fungal infection

Clin Microbiol Infect 2004; 10 (Suppl. 1): 107–117

INTRODUCTION Voriconazole was discovered in the late 1980s. The discovery process was started with the idea of developing an antifungal agent with a spectrum of activity beyond that of fluconazole. Like fluconazole, voriconazole belongs to the triazole class of drugs (Fig. 1). It is relatively insoluble in water, so the intravenous formulation contains voriconazole in a sulphobutylether b-cyclodextrin (SBECD) solute to allow for parenteral adminis- Fig. 1. Structural relationship between voriconazole and tration. fluconazole. The clinical development programme included the largest-ever randomised controlled trial in the 250-fold more active against the fungal demethy- treatment of invasive aspergillosis. The findings lase enzyme than against mammalian P450- of this trial demonstrate the significantly superior dependent steroid hormone biosynthesis efficacy of a clinical regimen that starts with [1]. voriconazole, over standard therapy starting with amphotericin B deoxycholate. SPECTRUM OF ACTIVITY

MECHANISM OF ACTION Voriconazole exhibits broad-spectrum activity at concentrations of £ 1mg⁄ L against the more Voriconazole selectively inhibits the fungal cyto- common fungal pathogens such as Candida spp. a chrome P450-dependent enzyme 14 -sterol deme- (including ﬂuconazole-resistant C. krusei) and thylase, thereby interrupting an essential step in is fungicidal to Aspergillus spp. as well as to ergosterol biosynthesis (Fig. 2). The drug is about Scedosporium and Fusarium spp. and certain other moulds (Fig. 3). The drug also exhibits good activity against less-common clinical iso- Corresponding author and reprint requests: J. P. Donnelly, lates, including Acremonium, Alternaria, Bipolaris, Department of Haematology, University Medical Center St Cladophialophora, Curvularia and Chrysosporium spp. Radboud, PO Box 9101, 6500 HB Nijmegen, the Netherlands [2], as well as the dimorphic fungi Histoplasma Tel: + 31 24 377 3384 Fax: + 31 24 354 2080 capsulatum, Blastomyces dermatitidis and Coccidio- E-mail: [email protected] ides immitis [3]. Voriconazole has little activity

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases 108 Clinical Microbiology and Infection, Volume 10 Supplement 1, 2004

Fig. 2. Mode of action of antifungal agents.

Fungus AMB FCZ ICZ VCZ PCZ CAN Candida albicans Candida tropicalis Candida parapsilosis ? Candida krusei Candida glabrata Cryptococcus neoformans Histoplasma capsulatum Blastomyces dermatitidis Coccidiodes immitis Paracoccidiodes brasiliensis ? Aspergillus fumigatus Zygomycetes Fusarium solani ? Scedosporium apiospermum AMB amphotericin B FCZ fluconazole ICZ itraconazole VCZ voriconazole PCZ posaconazole Fig. 3. Comparative spectrum of CAN candins activity in-vitro of antifungal agents. against Sporothrix schenckii [4] and the zygomyc- PHARMACOKINETIC PROPERTIES etes, such as Mucor, Rhizopus and Absidia spp. [2]. The pharmacokinetics of voriconazole are non- Correlating in-vitro activity with clinical out- linear, which leads to a greater than propor- come remains elusive because host factors other tional increase in exposure with increasing dose. than pathogen susceptibility are involved. Break- For instance, increasing the oral dose from points for voriconazole have yet to be estab- 200 mg to 300 mg twice daily leads to a 2.5- lished. fold increase in the area under the plasma

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 107–117 Donnelly and De Pauw Voriconazole – a new therapeutic agent 109 concentration-time curve (AUC). While there is The major metabolite of voriconazole is the a low intrapatient variability in plasma concen- N-oxide, which has negligible antifungal activity trations, the interindividual variability of voric- and accounts for 72% of the circulating radio- onazole pharmacokinetics is high. Population labelled metabolites in plasma. In all, metabolism pharmacokinetic data from therapeutic trials produces at least eight compounds without clin- have revealed no association between plasma ically significant antifungal activity. concentration and clinical outcome. The terminal half-life of voriconazole is dose dependent Excretion and is not predictive of its accumulation or elimination. Approximately 80% of a single, radiolabelled dose of voriconazole is excreted in the urine, almost completely as metabolites. Less than 2% of Absorption the dose is excreted in the urine as unchanged Voriconazole is rapidly and almost completely drug. The majority (> 94%) of the total radioac- absorbed following oral administration, with tivity is excreted in the first 96 h after both oral maximum plasma concentrations being achieved and intravenous dosing. Approximately 20% of 1–2 h after dosing. The oral bioavailability of the drug is excreted in the faeces. voriconazole is estimated to be 96%, which may permit switching between intravenous (IV) and CLINICAL STUDIES OF EFFICACY oral formulations when clinically appropriate. Absorption is not affected by changes in gastric The strategy of evaluating the efficacy and safety pH. As the presence of high-fat food affects of voriconazole for treating aspergillosis and can- voriconazole absorption, oral voriconazole should didiasis was rewarded by the drug being licensed not be taken within 1 h of a meal. for these indications. In addition, the results obtained from a study of documented invasive fungal infections with no approved antifungal Distribution therapy, or infections that were refractory to The volume of distribution at steady state for approved therapy (due to treatment failure or voriconazole is estimated to be 4.6 L ⁄ kg, suggest- intolerance of therapy), and from compassionate ing extensive distribution into tissues. Plasma use programmes indicate that voriconazole is an protein binding is estimated to be 58% and is important therapeutic option for treating predom- independent of dose or plasma concentrations. inantly fatal infections caused by other less The drug is also detectable in cerebrospinal fluid common moulds, including Fusarium and Scedos- samples (data on file). porium spp.

Metabolism Aspergillosis In-vitro studies showed that voriconazole is An open, noncomparative study of 116 patients metabolised by the hepatic cytochrome P450 with invasive aspergillosis resulted in an overall isoenzymes, CYP2C19, CYP2C9 and CYP3A4. efficacy of 48% (56 complete ⁄ partial responses) The isoenzyme CYP2C19 exhibits genetic poly- [6]. Fifty (60%) of the 84 patients with pulmonary morphism with 15–20% of Asian populations infection responded well to treatment with voric- being poor ⁄ slow metabolisers [5], whereas the onazole, 6 mg ⁄ kg twice a day on the first day, prevalence is much lower (3–5%) amongst Cau- followed by 3 mg ⁄ kg twice daily for 6–27 days casians and Blacks. Studies conducted in Cauca- and 200 mg twice daily, given orally for up to sian and Japanese healthy subjects have shown 24 weeks. The results obtained in this population, that poor metabolisers have, on average, four- which comprised newly diagnosed as well as fold higher voriconazole AUC than homozy- previously treated patients, compared favourably gous extensive metabolisers, while the AUC of to those achieved previously with other drugs heterozygous extensive metabolisers is two-fold [7–11]. Admittedly, differences in patient and higher than that of homozygous extensive metab- disease characteristics make comparisons difficult, olisers. but the response rate of 42% observed in the 19

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 107–117 110 Clinical Microbiology and Infection, Volume 10 Supplement 1, 2004 patients with aspergillosis of the central nervous system is promising. The results of this noncomparative study were confirmed in the largest randomised controlled trial ever undertaken for any antifungal agent in the primary treatment of invasive aspergillosis [12]. Ninety-five centres world-wide treated 391 immunocompromised patients with either voriconazole (given as two 6 mg ⁄ kg infusions 12 h apart on the first day, followed by 4 mg ⁄ kg every 12 h for at least 7 days, after which treatment could be continued orally 200 mg every 12 h) or 1–1.5 mg ⁄ kg ⁄ day amphotericin B deoxycholate given intravenously. The protocol-defined treatment period was 12 weeks. At the investigators’ discretion, initial randomised therapy could be switched to any other licensed therapy (lipid formulations of amphotericin B or itraconazole) when initial treatment was poorly tolerated or there was no response. Patients judged by an independent, blinded panel to have insufficient evidence to confirm their initial diagnosis of Fig. 4. Efficacy of voriconazole compared with ampho- aspergillosis were excluded from the ‘modified tericin B for treating invasive aspergillosis. intent-to-treat’ (MITT) population. These patients (50 randomised to voriconazole and 52 to amph- licensed therapy. By contrast, and not unexpect- otericin B) were not evaluated for efficacy. Hence, edly, 107 (80%) of patients who started in the 277 patients were included in the MITT popula- amphotericin B arm were switched to other tion and were evaluated for efficacy. licensed therapy. A satisfactory response (complete or partial Overall, fewer adverse events were reported for resolution of all attributable symptoms and signs patients receiving voriconazole, despite the longer and of radiographic or bronchoscopic abnormal- median duration of therapy, compared with ities present at baseline) was recorded for 76 (53%) amphotericin B. Although approximately 10 times of the 144 patients treated with voriconazole but more voriconazole patients (87, 45%) than amph- only for 42 (32%) of the 133 patients treated with otericin B patients (8, 4%) reported transient amphotericin B (P ¼ 0.0001; Fig. 4). Response visual disturbances (blurred vision, altered visual rates favoured voriconazole irrespective of whe- or colour perception, or photophobia, which all ther the diagnosis was considered proven or resolved spontaneously), the converse was true of probable, whether the infection was disseminated chills and fever, which affected 46 (25%) of those or pulmonary, and regardless of the underlying given amphotericin B, compared with six (3%)of condition, or presence of neutropenia. The those treated with voriconazole. Eighteen patients 12-week survival rate was also higher for the (9%) receiving voriconazole had an adverse event voriconazole group (71%, compared with 58% for of hypokalemia, compared with 47 (25%)on amphotericin B group; P ¼ 0.02). More than twice amphotericin B. Strikingly, seven patients (4%) as many patients (29%) randomised to amphoter- treated with voriconazole were recorded as hav- icin B died from invasive aspergillosis as those ing acute kidney failure, while this was consid- randomised to voriconazole (13%). ered an adverse event for 89 patients (48%) given Treatment with voriconazole was sustained amphotericin B ⁄ other licensed therapy. Serious longer, with a median duration of 77 days (range side-effects also affected more patients treated 2–84 days), compared with 10 days (range with amphotericin (45 patients; 24%) than with 1–84 days) for patients receiving amphotericin voriconazole (26 patients; 13%). Other adverse B. Fifty-two (36%) patients who started in events were infrequent and affected similar num- the voriconazole arm were switched to other bers in both groups.

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 107–117 Donnelly and De Pauw Voriconazole – a new therapeutic agent 111

transient visual changes affected almost a quarter Candidosis of those treated with voriconazole. Voriconazole has been shown to be as effective as Such studies are valuable for assessing the fluconazole for treating oesophageal candidiasis, safety of the drugs used, but are difficult to assess achieving a cure rate among endoscopy-con- in terms of efficacy since most patients do not have firmed cases of 113 of 115 patients (98.3%), a fungal disease. Moreover, some of the break- compared with 134 of 141 (95.0%) on fluconazole through infections may only represent the further [13]. Both drugs were generally well tolerated, manifestation of an infection that was already although 36 (18%) of the 159 patients treated with present, but undetected, at the start of empiric voriconazole experienced mild reversible visual therapy. The cases of fungal infection that occur abnormalities. Indeed, visual disturbance seems can lead to a better understanding of the drug’s characteristic of voriconazole, but studies have potential but this necessitates subgroup analysis shown no impact of long-term use on eye struc- and essentially results in a series of cases, which, ture or function. This side-effect may only prove as such, has limited statistical power. It also brings important to ambulatory patients who should not into question the rationale for using fever to guide drive or use machinery while affected [14]. antifungal therapy decision-making.

Scedosporium and Fusarium infections Experience in paediatric patients Sixteen of 28 patients treated with voriconazole Sixty-one paediatric patients aged 9 months up to for infections caused by S. apiospermum success- 15 years who had definite or probable invasive fully responded, as did two of seven patients fungal infections were treated with voriconazole. treated for S. prolificans infections (data on file). This population included 34 patients aged from 2 Seven of 17 patients were treated successfully to < 12 years old and 20 patients aged 12 to with voriconazole for infections due to Fusarium 15 years. The majority (57 ⁄ 61) had failed previous spp. Most of the patients had either been intoler- antifungal therapies. Therapeutic studies included ant of, or refractory to, prior antifungal therapy. five patients aged 12 to 15 years, the remaining In particular, the efficacy of voriconazole against patients received voriconazole in the compassio- potentially life-threatening infections by Scedospo- nate use programmes. Underlying diseases in rium spp. is striking. these patients included haematological malignancies and aplastic anaemia (27 patients) and chronic granulomatous disease (14 patients). The Empirical therapy most commonly treated fungal infection was Voriconazole and liposomal amphotericin B aspergillosis (43 ⁄ 61; 70%). (AmBisome) were also shown to be similarly effective for empiric therapy [15], although voric- Miscellaneous infections onazole failed to meet the statistical endpoint of noninferiority to the comparator across all com- Invasive aspergillosis involving the central ner- ponents of the study composite endpoint. Overall vous system is known to have a dismal outcome. A response rates were low, being 108 of 415 (26%) patient with acute leukaemia who developed a for voriconazole and 131 of 422 (31%) for cerebral abscess due to Aspergillus has been suc- AmBisome, and resolution of fever during cessfully treated [16]. In the study of Denning et al. neutropenia in only 137 (33%) and 152 (36%)of there were 19 cases of cerebral brain invasive episodes, respectively. Nonetheless, the survival aspergillosis, of which five were proven. Three rates were 87% and 90%, respectively. The patients (16%) had a partial response and five number of breakthrough fungal infections in achieved a stable response [6]. In a retrospective patients treated empirically with voriconazole study of eight consecutive cases of brain invasive was 8 (2%), compared with 21 (5%) for those on aspergillosis admitted to a single intensive-care liposomal amphotericin B. There were fewer unit between 1990 and 1999, all five treated before severe infusion-related reactions related to vorico- 1997 died [17]. Of the three survivors, two had nazole and less nephrotoxicity than was encoun- been treated with voriconazole and the other with tered with liposomal amphotericin B, although itraconazole, as had one of those who had died.

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 107–117 112 Clinical Microbiology and Infection, Volume 10 Supplement 1, 2004

More recently, in a study of refractory infections, dose of 4 mg ⁄ kg IV (or the closest equivalent in four of 12 patient (33%) with cerebral aspergillosis oral form) every 12 h is recommended for chil- had successful outcomes at the end of treatment dren aged between 2 and < 12 years of age. with voriconazole [18]. A case of brain abscess due Patients with mild to moderate hepatic cirrho- to Pseudallescheria boydii was successfully treated sis (Child–Pugh Class A or B) should receive the with surgical drainage and systemic voriconazole standard loading dose of voriconazole but the [19], as was an unusual case of chronic meningitis maintenance dose should be halved [21]. due to the same fungus [20]. Although far from Patients with moderate to severe renal dys- conclusive, these results offer hope of successful function (creatinine clearance < 50 mL ⁄ min) may treatment for a hitherto intractable disease. experience accumulation of the vehicle SBECD when given voriconazole intravenously. Oral voriconazole should be administered to these OFFICIAL LABELLING patients, unless the benefit of IV therapy out- AND INDICATIONS weighs the risk. Serum creatinine levels should be In Europe, voriconazole is indicated for the treat- closely monitored in these patients and considera- ment of invasive aspergillosis, fluconazole-resist- tion given to changing to oral therapy. ant serious invasive candida infections (including C. krusei), and serious fungal infections caused by Scedosporium and Fusarium spp. It is recommended INTERACTIONS that voriconazole should be administered primar- Effects of other medicinal products ily to immunocompromised patients with pro- on voriconazole gressive, possibly life-threatening infections. In the US, voriconazole is indicated for the treatment Voriconazole is metabolized by cytochrome P450 of invasive aspergillosis and serious fungal infec- isoenzymes, CYP2C19, CYP2C9 and CYP3A4. tions caused by S. apiospermum and Fusarium spp., Inducers or inhibitors of these isoenzymes may including F. solani, in patients intolerant of, or increase or decrease voriconazole plasma concen- refractory to, other therapy. trations, respectively. Rifampicin (a CYP450 inducer; 600 mg once daily) decreased the C (maximum plasma DRUG ADMINISTRATION max concentration) and AUCs (area under the plasma An intravenous loading dose of 6 mg ⁄ kg at concentration-time curve within a dose interval) 12-hourly intervals should be administered on of voriconazole by 93% and 96%, respectively day 1, followed by a maintenance dose of 4 mg ⁄ kg [22]. Coadministration of voriconazole and rif- 12-hourly. Voriconazole should be administered ampicin is contraindicated. Carbamazepine and at a maximum rate of 3 mg ⁄ kg per hour over phenobarbital are likely to significantly decrease 1–2 h. Maintenance therapy can be switched to plasma voriconazole concentrations and co- oral form at a dose of 200 mg 12-hourly (for administrationwithvoriconazoleiscontraindicated. ‡ patients 40 kg) or 100 mg 12-hourly (for patients Cimetidine increased voriconazole Cmax and < 40 kg). If therapy is initiated with the oral form, AUCs by 18% and 23%, respectively. No dosage a loading dose of 400 mg 12-hourly (200 mg adjustment of voriconazole is recommended. 12-hourly for patients < 40 kg) should be adminis- Ranitidine had no significant effect on voricon- s tered on day 1. Administration of a loading dose azole Cmax or AUC . on day 1 results in peak plasma concentrations The macrolide antibiotics erythromycin and close to steady state within 24 h. Treatment azithromycin had no significant effect on voric- s duration depends on the patient’s clinical and onazole Cmax and AUC . mycological response. Oral voriconazole should be taken at least 1 h before or after a meal. Effects of voriconazole on other medicinal products Special patient groups Voriconazole inhibits the activity of cytochrome No dosage adjustment is necessary based on P450 isoenzymes, CYP2C19, CYP2C9 and CYP3- gender or age ‡ 12 years; however, a maintenance A4. Thus, there is potential for voriconazole to

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 107–117 Donnelly and De Pauw Voriconazole – a new therapeutic agent 113 increase the plasma levels of substances metabo- Voriconazole may increase the plasma levels of lized by these CYP450 isoenzymes. sulphonylureas, such as tolbutamide, glipizide Coadministration of voriconazole with terfena- and glyburide, and therefore cause hypoglycae- dine, astemizole, cisapride, pimozide or quinidine mia. Careful monitoring of blood glucose is is contraindicated, because increased plasma recommended during coadministration. concentrations of these medicinal products can Voriconazole has been shown to inhibit lovast- lead to QTc prolongation and rare occurrences of atin metabolism in vitro in human liver micro- torsades de pointes. somes, therefore voriconazole is likely to increase Voriconazole increased sirolimus (2 mg single plasma levels of statins that are metabolised by s % % dose) Cmax and AUC by 556 and 1014 , CYP3A4. It is recommended that dose adjustment respectively. Coadministration of voriconazole of the statin be considered during coadministra- and sirolimus is contraindicated. tion. Increased statin levels have been associated Voriconazole may increase the plasma concen- with rhabdomyolysis. trations of ergot alkaloids (ergotamine and Althoughnotstudied clinically,voriconazolehas dihydroergotamine) and lead to ergotism. Coad- been shown to inhibit the metabolism of midazo- ministration of voriconazole with ergot alkaloids lam (a benzodiazepine) in vitro (human liver micro- is contraindicated. somes). Voriconazole is likely, therefore, to increase In stable renal transplant recipients, voriconaz- the plasma levels of benzodiazepines that are s ole increased cyclosporine Cmax and AUC by at metabolized by CYP3A4 (e.g. midazolam and tria- least 13% and 70%, respectively. When initiating zolam) and lead to a prolonged sedative effect. It is voriconazole in patients already receiving recommended that dose adjustment of the benzo- cyclosporine, it is recommended that the cyclosp- diazepine be considered during coadministration. orine dose be halved and that the cyclosporine Voriconazole may increase the plasma levels of level be carefully monitored [23]. Increased the vinca alkaloids (e.g. vincristine and vinblas- cyclosporine levels have been associated with tine) and lead to neurotoxicity. s nephrotoxicity. When voriconazole is discontin- Voriconazole increased Cmax and AUC of pre- ued, cyclosporine levels must be carefully mon- dnisolone (60 mg single dose) by 11% and 34%, itored and the dose increased as necessary. respectively. No dosage adjustment is recommen- Voriconazole increased tacrolimus Cmax and ded [27]. s % % AUC by 117 and 221 , respectively. When Voriconazole had no significant effect on Cmax initiating voriconazole in patients already receiv- and AUCs of digoxin (0.25 mg once daily) [28] or ing tacrolimus, it is recommended that the tacr- mycophenolic acid (a UDP-glucuronyl transferase olimus dose be reduced to a third of the original substrate; 1 g single dose) [29]. dose and that the tacrolimus level be carefully monitored [24,25]. Increased tacrolimus levels Two-way interactions have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus levels Phenytoin (CYP2C9 substrate and potent CYP450 must be carefully monitored and the dose inducer) increased as necessary. Concomitant use of voriconazole and pheny- Coadministration of voriconazole with warfarin toin should be avoided unless the benefit out- (an anticoagulant) increased the maximum pro- weighs the risk. Careful monitoring of phenytoin thrombin time by 93%. Close monitoring of pro- plasma levels is recommended when phenytoin is thrombin time is recommended if warfarin and coadministered with voriconazole. Phenytoin may voriconazole are coadministered [26]. Voriconaz- be coadministered with voriconazole if the main- ole may increase the plasma concentrations of tenance dose of voriconazole is increased to coumarins, such as phenprocoumon and acen- 5mg⁄ kg intravenously twice daily or from ocoumarol, and therefore may cause an increase in 200 mg to 400 mg orally, twice daily (100 mg to prothrombin time. If patients receiving coumarin 200 mg orally, twice daily in patients < 40 kg) [30]. preparations are treated simultaneously with voriconazole, the prothrombin time should be monit- Rifabutin (CYP450 inducer) ored at close intervals and the dosage of Concomitant use of voriconazole and rifabutin anticoagulants should be adjusted accordingly. should be avoided unless the benefit outweighs the

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 107–117 114 Clinical Microbiology and Infection, Volume 10 Supplement 1, 2004 risk. If rifabutin coadministration with voriconaz- and efavirenz. Although not studied, the metabo- ole is justified then the maintenance dose of lism of voriconazole may be induced by efavirenz voriconazole may be increased to 5 mg ⁄ kg intra- and nevirapine. Voriconazole may also inhibit the venously twice daily or from 200 mg to 350 mg metabolism of NNRTIs. Due to the lack of in-vivo orally, twice daily (100 mg to 200 mg orally, twice studies, patients should be carefully monitored daily in patients less than 40 kg). Careful monitor- for any occurrence of drug toxicity and ⁄ or lack of ing of full blood counts and adverse events to ri- efficacy during the coadministration of voricon- fabutin (e.g. uveitis) is recommended when azole and NNRTIs. rifabutin is coadministered with voriconazole [22]. ADVERSE EXPERIENCES Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate) Data on the safety of voriconazole is derived from Omeprazole (40 mg once daily) increased voric- 2000 subjects, of whom 1493 were patients treated s % % onazole Cmax and AUC by 15 and 41 , in therapeutic trials [34]. The most commonly respectively. No dosage adjustment of voriconaz- reported adverse events are displayed in Table 1. ole is recommended. Voriconazole increased Visual disturbances, dermatological reactions and s % % omeprazole Cmax and AUC by 116 and 280 , liver function test abnormalities were common. respectively. When initiating voriconazole in Age, race and gender had no influence on the patients already receiving omeprazole, it is nature or frequency of adverse events. recommended that the omeprazole dose be halved [31,32]. The metabolism of other proton Visual disturbances pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole. In clinical trials, approximately 30% of subjects experienced altered ⁄ enhanced visual perception, Indinavir (CYP3A4 inhibitor and substrate) blurred vision, colour vision change, or photo- Indinavir (800 mg three times daily) had no a significant effect on voriconazole Cmax,Cmin and Table 1. Treatment-emergent adverse events reported by AUCs. Voriconazole did not have a significant at least 1% of patients in voriconazole therapeutic studies, s by body system (n ¼ 1493) effect on Cmax and AUC of indinavir (800 mg three times daily) [33]. Special senses Abnormal vision (20.6%); Photophobia (2.4%); Other HIV protease inhibitors (CYP3A4 inhibitors) Chromatopsia (1.3%) In-vitro studies suggest that voriconazole may Body as a whole Fever (6.2%); Chills (4.1%); Headache (3.2%); inhibit the metabolism of human immunode- Abdominal pain (1.7%) ficiency virus (HIV) protease inhibitors (e.g. Cardiovascular system saquinavir, amprenavir and nelfinavir). In-vitro Tachycardia (2.5%); Hypertension (1.9%); Hypotension % % studies also show that the metabolism of voric- (1.7 ); Vasodilatation (1.5 ) Digestive system onazole may be inhibited by HIV protease Nausea (5.9%); Vomiting (4.8%); Liver function tests inhibitors. Results of the combination of voric- abnormal (2.7%); Diarrhoea (1.1%); Cholestatic jaundice onazole with other HIV protease inhibitors, (1.1%); Dry mouth (1.0%) however, cannot be predicted in humans only Metabolic and nutritional systems % from in-vitro studies. Patients should be care- Alkaline phosphatase increased (3.6 ); Hepatic enzymes increased (1.9%); ASAT (SGOT) increased (1.9%); ALAT fully monitored for any occurrence of drug (SGPT) increased toxicity and ⁄ or loss of efficacy during the (1.8%); Hypokalaemia (1.6%); Peripheral oedema (1.1%); coadministration of voriconazole and HIV pro- Hypomagnesaemia (1.1%) tease inhibitors. Nervous system Hallucinations (2.5%); Dizziness (1.3%) Skin and appendages Non-nucleoside reverse transcriptase inhibitors Rash (5.8%); Pruritus (1.1%); Maculopapular rash (1.1%)

(NNRTI) (CYP3A4 substrates, inhibitors or CYP450 a inducers) Events recorded as possibly related to therapy or of unknown causality. In-vitro studies show that the metabolism of ASAT, aspartate aminotransferase; ALAT, alanine trans- voriconazole may be inhibited by delavirdine aminase.

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 107–117 Donnelly and De Pauw Voriconazole – a new therapeutic agent 115 phobia. The visual disturbances usually occurred fungal infection. Essentially, there are three clas- around half an hour after administration of ses of drugs—the polyenes (amphotericin B in its voriconazole, usually spontaneously resolved various forms), the triazoles (fluconazole, itracon- within an hour, and were commonest during azole and voriconazole), and the candins (caspo- the first week of treatment [14]. The reactions are fungin)—and two strategies available to us, one generally mild, seldom necessitating stopping that relies entirely on intravenous therapy and the treatment, are transient and completely reversi- other that aims to switch from parenteral to oral ble, and do not appear to lead to long-term treatment. Each class of drug can be employed sequelae. The mechanism behind these reactions parenterally but only the azoles can be used to is unknown. Visual disturbances may be associ- complete the second strategy. ated with higher plasma concentrations and ⁄ or The frustration at not being able to identify doses. patients with mould infections at an early stage may drive clinicians to resort to giving voriconazole for prophylaxis, even though there are no Dermatological reactions clinical data available on the use of the drug in Mild or moderate dermatological reactions tend this setting. Early detection, resulting in early to affect patients with serious underlying diseases initiation of treatment, is crucial in the manage- who were receiving various other medications. ment of many mould infections, and is likely to Serious cutaneous reactions, including Stevens– remain an area of focus in the future. The true Johnson syndrome, toxic epidermal necrolysis, and value of voriconazole may only become apparent erythema multiforme, are rare. Photosensitivity once management strategies achieve a better reactions have been reported, especially during balance between diagnosis and treatment, and long-term treatment. risks are better defined so that patients who need therapy are treated optimally, and those who do not need it are identified and spared unnecessary Liver function tests exposure to antifungal agents. Liver function test abnormalities were seen in Voriconazole represents a clear advance in the 13.4% of trial subjects, and may be associated treatment of invasive aspergillosis, with proven with higher plasma concentrations or dosages of superiority over amphotericin B, in terms of both voriconazole. Liver function test abnormalities efficacy and patient survival. The study compar- resolved either without any alterations in dosage ing voriconazole and amphotericin B for primary or after dose adjustment or stopping treatment therapy of invasive aspergillosis, which is the (seldom required). Voriconazole has been infre- largest therapeutic study undertaken of this quently associated with cases of serious hepatic disease, also indicated that voriconazole is toxicity in patients with other serious underlying better tolerated than amphotericin B [12]. Des- conditions. This includes cases of jaundice, and pite the median duration of therapy being longer rare cases of hepatitis and hepatic failure leading in patients randomised to voriconazole than in to death. those randomised to amphotericin B, there were still significantly fewer treatment-related adverse events in the voriconazole arm (343, Infusion-related reactions compared with 421 in the amphotericin B arm; As with other drugs, anaphylactic reactions such P ¼ 0.02). as flushing, fever, sweating and tachycardia have The population included in the invasive asper- occurred rarely, immediately upon starting an gillosis study [12] included severely ill patients. infusion of voriconazole. Due to their underlying conditions, such patients are liable to receive numerous concomitant medications, and are prone to drug–drug interactions THE PLACE OF VORICONAZOLE and adverse events related to their antifungal Compared with a decade ago, we seem to be therapy. Consequently, this population is difficult spoiled for choice when it comes to antifungal to treat, and previous clinical studies in these drugs, but appearances can be deceptive, especi- patients have been almost exclusively limited to ally when considering the treatment of invasive trials using amphotericin B. The availability of oral

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 107–117 116 Clinical Microbiology and Infection, Volume 10 Supplement 1, 2004 and intravenous formulations of voriconazole Voriconazole is clearly a valuable and import- means that the therapeutic options available ant addition to the limited armamentarium cur- for the most seriously ill patients are increased. rently at our disposal, and the information we Earlier studies of azole therapy for invasive now have about this agent is sufficiently compel- aspergillosis, using itraconazole, could not include ling for it to earn a place in any antifungal the most severely ill patients, due to the lack of an management strategy. IV formulation (oral dosing is not possible for the most ill). In one such study, 30 (39%)of76 REFERENCES evaluable patients had a complete or partial response at the end of treatment with oral itrac- 1. Ghannoum MA, Kuhn DM. Voriconazole—better chances onazole, 600 mg ⁄ day for 4 days, followed by for patients with invasive mycoses. Eur J Med Res 2002; 7: ⁄ 242–56. 400 mg day [35]. Even though this study cannot 2. Wildfeuer A, Seidl HP, Paule I, Haberreiter A. In vitro be compared directly with the voriconazole study evaluation of voriconazole against clinical isolates of [12], the higher proportion of patients with a yeasts, moulds and dermatophytes in comparison with satisfactory response rate to voriconazole (76 ⁄ 144 itraconazole, ketoconazole, amphotericin B and griseoful- patients, 53%) is particularly striking, considering vin. Mycoses 1998; 41: 309–19. 3. Li RK, Ciblak MA, Nordoff N, Pasarell L, Warnock DW, the severely ill patient population enrolled in the McGinnis MR. In vitro activities of voriconazole, itracon- latter study. Although an intravenous formulation azole, and amphotericin B against Blastomyces dermatitidis, of itraconazole has now been developed, its use to Coccidioides immitis, and Histoplasma capsulatum. Antimicrob treat invasive aspergillosis has only been evalu- Agents Chemother 2000; 44: 1734–6. 4. McGinnis MR, Nordoff N, Li RK, Pasarell L, Warnock DW. ated in a relatively small-scale (31 patients), Sporothrix schenckii sensitivity to voriconazole, itraconazole noncomparative study [36,37]. and amphotericin B. Med Mycol 2001; 39: 369–71. In addition to its efficacy in the treatment of 5. Balian JD, Sukhova N, Harris JW et al. The hydroxylation infections caused by Aspergillus [6,12] and Candida of omeprazole correlates with S-mephenytoin metabo- spp. [13], voriconazole also constitutes a poten- lism: a population study. Clin Pharmacol Ther 1995; 57: 662–9. tially life-saving therapy for patients with infec- 6. Denning DW, Ribaud P, Milpied N et al. Efficacy and tions caused by less-common fungal pathogens. safety of voriconazole in the treatment of acute invasive A recent study has demonstrated the efficacy of aspergillosis. Clin Infect Dis 2002; 34: 563–71. voriconazole in treating patients with documen- 7. Chopra R, Fielding A, Goldstone AH. Successful treatment of fungal infections in neutropenic patients with liposomal ted invasive fungal infections with no approved amphotericin (AmBisome)–a report on 40 cases from a antifungal therapy or infections that were refract- single centre. Leuk Lymphoma 1992; 7 (Suppl.): 73–7. ory to approved therapy (due to treatment failure 8. Denning DW, Tucker RM, Hanson LH, Stevens DA. or intolerance of therapy) [18]. Despite the seri- Treatment of invasive aspergillosis with itraconazole. Am J ously ill patient population, and the high risk of Med 1989; 86: 791–800. % 9. Mehta J, Kelsey S, Chu P et al. Amphotericin B lipid treatment failure (approximately 75 of the 301 complex (ABLC) for the treatment of confirmed or pre- patients evaluated for efficacy had failed to sumed fungal infections in immunocompromised patients respond to other antifungal agents), there was with hematologic malignancies. Bone Marrow Transplant an overall survival rate of 66% 90 days after 1997; 20: 39–43. 10. Oppenheim BA, Herbrecht R, Kusne S. The safety and starting voriconazole therapy, and a satisfactory efficacy of amphotericin B colloidal dispersion in the global response rate of 50%. Efficacy rates by treatment of invasive mycoses. Clin Infect Dis 1995; 21: pathogen in this study included 62 ⁄ 142 (43.7%) 1145–53. and 50 ⁄ 87 (57.5%) for refractory aspergillosis and 11. Wong-Beringer A, Jacobs RA, Guglielmo BJ. Lipid formulations of amphotericin B: clinical efficacy and toxici- candidiasis, respectively, 9 ⁄ 10 (90%) for penicil- ⁄ % ⁄ % ties. Clin Infect Dis 1998; 27: 603–18. liosis, 5 11 (45 ) for fusariosis, and 3 10 (30 ) 12. Herbrecht R, Denning DW, Patterson TF et al. Voriconaz- for scedosporiosis. Again, voriconazole was ole versus amphotericin B for primary therapy of invasive acceptably tolerated, despite the diverse nature aspergillosis. N Engl J Med 2002; 347: 408–15. of the patients studied and their severe illnesses. 13. Ally R, Schu¨ rmann D, Kreisel W et al. A randomized, double-blind, double-dummy, multicenter trial of voric- Although visual events and elevated liver func- onazole and fluconazole in the treatment of esophageal tion test results were observed, if monitored candidiasis in immunocompromised patients. Clin Infect closely, these findings rarely developed into Dis 2001; 33: 1447–54. serious adverse events, even in this complex 14. Tomaszewski K, Purkins L. Visual effects with voriconazole [Abstract A-639]. In: Program and Abstracts of the 41st patient group.

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 107–117 Donnelly and De Pauw Voriconazole – a new therapeutic agent 117

Interscience Conference on Antimicrobial Agents and Chemo- Conference on Antimicrobial Agents and Chemotherapy. Chi- therapy. Chicago, IL: American Society of Microbiology, cago, IL: American Society of Microbiology, 2001; 2. 2001; 20. 26. Purkins L, Wood N, Kleinermans D, Nichols D. Vorico- 15. Walsh TJ, Pappas P, Winston DJ et al. Voriconazole com- nazole potentiates warfarin-induced prothrombin time pared with liposomal amphotericin B for empirical anti- prolongation. Br J Clin Pharmacol 2003; 56 (Suppl. 1): 24–9. fungal therapy in patients with neutropenia and persistent 27. Ghahramani P, Purkins L, Kleinermans D et al. The fever. N Engl J Med 2002; 346: 225–34. pharmacokinetics of voriconazole and its effect on 16. Schwartz S, Milatovic D, Thiel E. Successful treatment of prednisolone disposition [Abstract 842]. In: Program and cerebral aspergillosis with a novel triazole (voriconazole) Abstracts of the 40th Interscience Conference on Antimicrobial in a patient with acute leukaemia. Br J Haematol 1997; 97: Agents and Chemotherapy. Toronto, Ont.: American Society 663–5. of Microbiology, 2000: 23. 17. Tattevin P, Bruneel F, Lellouche F et al. Brain aspergillosis: 28. Purkins L, Wood N, Kleinermans D, Nichols D. Vorico- Impact of azole therapy [Abstract M-869]. In: Program and nazole does not affect the steady-state pharmacokinetics of Abstracts of the 42nd Interscience Conference on Antimicrobial digoxin. Br J Clin Pharmacol 2003; 56 (Suppl. 1): 45–50. Agents and Chemotherapy. San Diego, CA: American Society 29. Wood N, Abel S, Fielding A et al. Voriconazole does of Microbiology, 2002; 388. not affect the pharmacokinetics of mycophenolic acid 18. Perfect JR, Marr KA, Walsh TJ et al. Voriconazole treat- [Abstract A-24]. In: Program and Abstracts of the 41st Inter- ment for less-common, emerging, or refractory fungal science Conference on Antimicrobial Agents and Chemotherapy. infections. Clin Infect Dis 2003; 36: 1122–31. Chicago, IL: American Society of Microbiology, 2001; 3. 19. Nesky MA, McDougal EC, Peacock JE Jr. Pseudallescheria 30. Purkins L, Wood N, Ghahramani P et al. Coadministration boydii brain abscess successfully treated with voriconazole of voriconazole and phenytoin: pharmacokinetic inter- and surgical drainage: case report and literature review of action, safety, and toleration. Br J Clin Pharmacol 2003; 56; central nervous system pseudallescheriasis. Clin Infect Dis (Suppl. 1): 37–44. 2000; 31: 673–7. 31. Wood N, Tan K, Purkins L et al. Effect of omeprazole on 20. Poza G, Montoya J, Redondo C et al. Meningitis caused by the steady state pharmacokinetics of voriconazole. Br J Pseudallescheria boydii treated with voriconazole. Clin Infect Clin Pharmacol 2003; 56 (suppl. 1): 56–61. Dis 2000; 30: 981–2. 32. Wood N, Tan K, Allan R et al. Effect of voriconazole on the 21. Tan KKC, Wood N, Weil A. Multiple-dose pharmacoki- pharmacokinetics of omeprazole [Abstract A-19]. In: Pro- netics of voriconazole in chronic hepatic impairment gram and Abstracts of the 41st Interscience Conference on [Abstract A-16]. In: Program and Abstracts of the 41st Inter- Antimicrobial Agents and Chemotherapy, Chicago, IL: science Conference on Antimicrobial Agents and Chemotherapy. American Society of Microbiology, 2001; 2. Chicago, IL: American Society of Microbiology, 2001; 1. 33. Purkins L, Wood N, Kleinermans D, Love ER. No clinically 22. Ghahramani P, Purkins L, Kleinermans D et al. Effects of signiﬁcant pharmacokinetic interactions between vorico- rifampicin and rifabutin on the pharmacokinetics of vor- nazole and indinavir in healthy volunteers. Br J Clin iconazole [Abstract 844]. In: Program and Abstracts of the Pharmacol 2003; 56 (Suppl. 1): 62–8. 40th Interscience Conference on Antimicrobial Agents and 34. Tomaszewski K, Nurbhai N, Baruch A. The overall clinical Chemotherapy. Toronto, Ont.: American Society of Micro- safety of voriconazole [Abstract 123]. Presented at the biology, 2000: 23. Tandem BMT Meetings, Orlando, FL, USA. Biol Blood Mar- 23. Romero AJ, Pogamp PL, Nilsson LG, Wood N. Effect of row Transplant 2002; 8: 95–6. voriconazole on the pharmacokinetics of cyclosporine in 35. Denning DW, Lee JY, Hostetler JS et al. NIAID Mycoses renal transplant patients. Clin Pharmacol Ther 2002; 71: 226– Study Group multicenter trial of oral itraconazole therapy 34. for invasive aspergillosis. Am J Med 1994; 97: 135–44. 24. Wood N, Tan K, Allan R et al. Effect of Voriconazole on 36. Caillot D, Bassaris H, McGeer A et al. Intravenous itrac- the pharmacokinetics of tacrolimus [Abstract A-20]. In: onazole followed by oral itraconazole in the treatment of Program and Abstracts of the 41st Interscience Conference on invasive pulmonary aspergillosis in patients with hema- Antimicrobial Agents and Chemotherapy. Chicago, IL: tologic malignancies, chronic granulomatous disease, or American Society of Microbiology, 2001; 2. AIDS. Clin Infect Dis 2001; 33: e83–90. 25. Singh N, Zhang S, Gayowski T, Venkataramanan R. Vor- 37. Caillot D. Intravenous itraconazole followed by oral iconazole inhibition of tacrolimus metabolism after liver itraconazole for the treatment of amphotericin-B-refractory transplantation and in human liver microsomes [Abstract invasive pulmonary aspergillosis. Acta Haematol 2003; 109: A-21]. In: Program and Abstracts of the 41st Interscience 111–18.

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 107–117