New agents for treatment and prevention and their pediatric development

New antifungal triazoles

Voriconazole

Voriconazole (Vfend™) (Fig. 2) is a recently approved synthetic antifungal triazole with activity against a wide spectrum of clinically important yeasts and moulds, including Candida spp., Cryptococcus neoformans, Aspergillus and other hyaline moulds, dematiaceous moulds as well as dimorphic moulds (Tab. 7), both in vitro as well as in animal models. A notable exemption are the zygomycetes, against which voriconazole is intrinsically inactive. Similar to itraconazole, voriconazole is generally considered fungistatic against Candida but fungicidal against Aspergillus spp. [214, 320].

Voriconazole is available in oral and IV formulations; oral bioavailability exceeds 90% in the fasted state. In adults, the compound has nonlinear pharmacokinetics. Plasma protein binding is 58%, and the mean volume of distribution accounts for 2 L/kg. Tissue and CSF levels exceed those of trough plasma levels several fold. The plasma half-life is 6 h, with elimination primarily occurring by oxidative hepatic metabolism to at least eight metabolites that are eliminated via the urine; less than 2% of a dose of voriconazole are excreted unchanged in urine. The major isoenzyme involved in voriconazole metabolization is CYP2C19, but CYP2C9 and CYP3A4 also contribute. There is a wide between-subject variability in the disposition of voriconazole, that is related to genetic CYP2C19 polymorphism (Tab. 8) [214, 321].

Voriconazole has an acceptable safety profile. The accrued clinical data indicate that side effects include four distinct clinical categories: Transient

Figure 2. Structural formulas of voriconazole and posaconazole and, for comparison, those of fluconazole and itraconazole.

liver enzyme abnormalities (10-20%), skin reactions (< 10%), hallucinations or confusion (< 10%) and transient, dose-related visual disturbances (altered or enhanced perception of light, blurred vision; 25-45%) [214]. However, drug-related adverse effects requiring the discontinuation of voriconazole were infrequent in comparative clinical trials (2-13%) [322-324]. Voriconazole is both substrate and inhibitor of CYP2C19, CYP2C9, and CYP3A4, and therefore, a number of clinically relevant and potentially hazardous drug-drug interactions need to be considered [214].

Voriconazole has demonstrated excellent clinical efficacy in Phase II and III clinical trials in patients with OPC [325] and esophageal candidiasis [322]. In salvage studies of invasive aspergillosis and other mycoses, responses were observed in 41-55% of patients [326, 327]. A multinational, randomized Phase III clinical trial of voriconazole and conventional amphotericin B followed by other licensed antifungal therapy for primary therapy of invasive aspergillosis revealed superior antifungal efficacy and improved survival of voriconazole-treated patients at week 12 [323]. A randomized comparative study of voriconazole versus conventional amphotericin B followed by fluconazole for treatment of candidemia in non-neutropenic patients showed similar response rates and end of treatment and similar survival at 3 months [328]. In a large international collaborative study of voriconazole versus liposomal amphotericin B for empirical therapy, voriconazole did not

Table 7. Principal activity in vitro of new antifungal agents

Voriconazole

Posa-conazole

Caspo-fungin

Anidula-fungin

Micafungin

Aspergillus spp.

+

+

+

+

+

Candida spp.

+

+

+

+

+

C. glabrata

+

+

+

+

+

C. krusei

+

+

+

+

+

Cryptococcus neoformans

+

+

-

-

-

Non-Aspergillus hyalo-hyphomycetes

+/-

+/-

-

-

-

Fusarium spp.

+/-

+/-

-

-

-

Scedosporium spp.

+/-

+/-

-

-

-

Phaeohyphomycetes ('black moulds')

+

+

+/-

+/-

+/-

Zygomycetes

-

+

-

-

-

Dimorphic ('endemic') moulds

+

+

+/-

+/-

+/-

+, generally active; +/-, variable activity; -, no known activity as single agent at concentrations achieved in human subjects following standard dosages.

Table 8. Principal pharmacokinetic properties of new antifungal triazoles and echinocandins

Vori-conazole

Posa-conazole

Caspo fungin

Anidula-fungin

Micafungin

Formulation

PO/IV

PO (IV)

IV

IV

IV

Dose linearity

No

Yes

Yes

Yes

Yes

Oral bioavailability (%)

> 90

> 50

n/a

n/a

n/a

Protein binding (%)

58

> 95

97

84

99

Volume of distribution

(L/kg)

2

> 5

n/a

0.7-0.9

0.24

Elimination half-life (h)

6

25

8-10

24

15

Substrate / inhibitor of CYP450

3A4,2C9, 2C19

3A4

n/a

n/a

- urine (%/% metabolites)

<20/? 80/78

77/14/14

Degradation/meta-bolization, urine > feces

Degradation only, feces

Meta-bolization, feces > urine

n/a, not applicable n/a, not applicable meet the prespecified statistical endpoint for non-inferiority in a composite endpoint , but was associated with significantly fewer breakthrough invasive fungal infections, particularly those due to invasive aspergillosis [324]. Finally, several reports also suggest the potential usefulness of voriconazole for treatment of infections by unusual hyaline and dematiaceous fungi [327], and for treatment of cerebral mould infections [329].

Voriconazole is approved for treatment of invasive aspergillosis, fusari-osis, and scedosporiosis, and for primary treatment of invasive candidiasis in non-neutropenic patients (Tabs 2-4). The recommended IV dosages for patients of a 12 years are 6 mg/kg bid on day 1, followed by 4 mg/kg bid. The oral dosages in adults are 400 mg bid on day 1 (< 40 kg: 200 mg bid), followed by 200 mg bid (< 40 kg: 100 mg bid). In patients with renal insufficiency, no dosage adjustment is needed for the PO formulation; because of the renal clearance of the IV carrier, patients with a creatinine clearance of < 50 mL/ min should receive voriconazole by the oral route. In patients with mild to moderate hepatic function abnormalities, half of the daily maintenance dosage is recommended after the initial loading dose. Recommendations for severe liver failure are lacking [320].

Pediatric patients of < 12 years have a higher capacity for elimination of voriconazole per kilogram of body weight than adult healthy volunteers, resulting in a lower, potentially non-therapeutic exposure at similar dosages [330]. An intraindividual dosage escalation study exploring pharmacokinet-ics and safety of higher dosage regimens of voriconazole in this patient population has been completed. Based on that study, an IV dosage of 7 mg/kg bid and an oral dosage of 200 mg bid (oral suspension) without loading dose is recommended for children < 12 years of age [331]. Voriconazole has been administered safely and with success to a number of children < 12 years of age without therapeutic alternative. Of 58 immunocompromised children with proven or probable invasive fungal infection refractory to or intolerant of conventional antifungal therapy, 26 patients (45%) had a complete or partial response. Four patients (7%) were discontinued because of intolerance. A total of 23 patients had voriconazole-related adverse events, most commonly elevation in hepatic transaminases or bilirubin (n = 8), skin rash (n = 8), abnormal vision (n = 3) and photosensitivity reactions (n = 3) [332]. The safety and tolerance of voriconazole were further analyzed in a retrospective cohort study of 37 immunocompromised children and adolescents requiring voriconazole therapy for various indications. Voriconazole was administered intravenously and/or orally at dosages ranging from 2 to 8 mg/kg bid for a mean duration of 174 days (range, 5-998 days). Grade I or II adverse events were observed in 19 patients (51%); the most frequent events included transient increases in hepatic transaminases (19) and transient visual disturbances (5). Four patients (10%) experienced grade III/IV adverse events and 3 (8%) were permanently discontinued. While not a primary endpoint of the analysis, voriconazole showed promising efficacy as preventive and therapeutic modality [333].

Posaconazole

Posaconazole (Noxafil™) (Fig. 2) is a novel lipophilic antifungal triazole with potent and broad-spectrum activity against opportunistic, endemic, and dermatophytic fungi in vitro. This activity extends to organisms that are often refractory to existing triazoles, amphotericin B or echinocandins such as C. glabrata, C. krusei, A. terreus, and Fusarium spp. Importantly, posacon-azole also possesses activity against zygomycetes both in vitro and in vivo, distinguishing it from all available azoles (Tab. 7) [334, 335].

Posaconazole is available as oral suspension only and achieves optimal exposure when administered in two to four divided doses given with food or a nutritional supplement. The compound has a large volume of distribution in the order of 5 L/kg and a prolonged elimination half-life of approximately 20 h. Posaconazole is not metabolized through the cytochrome P450 enzyme system but primarily excreted in unchanged form in the feces. It is inhibitory against cytochrome P3A4, but has no effects on 1A2, 2C8, 2C9, 2D6 and 2E1 isoenzymes, and, therefore, a limited spectrum of drug-drug interactions can be expected (Tab. 8) [336, 337].

Posaconazole appears to be well tolerated in a manner comparable to fluconazole. The overall safety of posaconazole has been assessed in more than 400 patients with invasive fungal infections from two open label clinical trials [338]. Treatment-related adverse events occurred in 38% of patients (164/428); the most common were nausea (8%), vomiting (6%), headache (5%), abdominal pain (4%), and diarrhea (4%). Treatment-related abnormal liver function test results were observed in up to 3% of patients. Serious adverse events considered possibly or probably related to PCZ occurred in 35 (8%) patients. The drug-drug interaction potential of posaconazole has been investigated in seven open label, cross-over drug interaction studies. As with other azoles, caution is advised when posaconazole is coadminis-tered with CYP3A4 substrates (increased levels of coadministered drugs) and unspecific enzyme inducers (decreased levels of posaconazole) [334].

Apart from two Phase II clinical trials for first- [339] and second line [340] therapy of HIV-associated OPC and esophageal candidiasis, preliminary results have been presented for the pivotal Phase II salvage study in patients with possible, probable and proven invasive fungal infections refractory to or intolerant of standard therapies [341] and a Phase III randomized clinical trial comparing posaconazole to fluconazole for treatment of OPC [342]. Posaconazole has demonstrated strong antifungal efficacy in Phase II and III clinical trials in immunocompromised patients with OPC and esophageal candidiasis. Posaconazole also showed promising efficacy as salvage therapy in a large Phase II study including 330 patients with invasive fungal infections intolerant to or refractory to standard therapies and a contemporaneous external control of 279 patients [341]. Most patients (86%) were refractory to previous therapy. Successful outcomes at end of treatment in the posaconazole and in the contemporaneous external control cohorts were 42% vs. 26% in aspergillosis (107 and 86 patients), 39% vs. 50% in fusariosis (18 vs. 4 patients), 56% vs. 50% in zygomycoses (11 vs. 8 patients), 69% vs. 43% (16 vs. 7 patients) in coccidioidomycosis, 52% vs. 53% in candidiasis (23 vs. 30 patients), 48% vs. 58% in cryptococcosis (31 vs. 64 patients), 81% vs. 0% in chromoblastomycosis (11 vs. 2 patients), and 64% vs. 60% in other invasive fungal infections (30 vs. 20 patients). A retrospective analysis of the manufacturer's compassionate use program including 91 patients with proven or probable zygomycosis refractory or intolerant to prior antifungal therapy revealed a 60% success rate (complete and partial responses) at 12 weeks after initiation of therapy, supporting the usefulness of posaconazole for second line or consolidation therapy of zygomycosis [343]. Preventative randomized Phase III studies in high-risk patients with HSCT and GVHD [344] and acute leukemias [345] have been completed. In the first study, patients received either posaconazole 200 mg tid or flu-conazole 400 mg/day, respectively, with the start of immunosuppression for a total of 16 weeks. Treatment with posaconazole led to a decreased incidence of invasive fungal infections at 16 weeks (5% vs. 9%, p = 0.07), with a statistically significant decrease in invasive Aspergillus infections (2 vs. 7%, p = 0.006). At 7 days after the end of treatment, fewer patients had invasive fungal disease (2 vs. 8%, p = 0.004), and fewer patients had invasive aspergillosis (1 vs. 6%, p = 0.001). There were no differences in overall mortality at 12 weeks, and no differences in the rate of drug discontinuations due to adverse events between the two study arms. In the second study, patients received posaconazole 200 mg tid and either fluconazole 400 mg/day or itraconazole 200 mg bid, respectively. Treatment was started with each cycle following drop of the absolute neutrophil count (ANC) to s 500 ^L for up to 12 weeks. Significantly fewer patients enrolled in the posaconazole arm developed an invasive fungal infection at day 7 after the end of treatment as compared to the comparator arm (2% vs. 8%, p < 0.01); most importantly, treatment with posaconazole resulted in a significant decrease in the rate of invasive aspergillosis (1% vs. 7%, p < 0.001). At day +100 after randomization, the rate of invasive fungal infections was 5% and 11% (p < 0.01), and patients treated with posaconazole had a significantly improved survival probability (p = 0.035). These two landmark studies demonstrate the pre-ventative efficacy of posaconazole in particular against invasive Aspergillus infections in high risk patients, and a survival benefit in patients with acute myeloblastic leukemia/myelodysplastic syndrome undergoing remission induction chemotherapy.

Posaconazole has recently been approved in the European Union for treatment of aspergillosis, fusariosis, chromoblastomycosis and coccidioi-domycosis refractory to or intolerant of standard therapies; it is approved for prophylaxis in neutropenic patients with AML/MDS and in HSCT patients with GVHD grades II to IV in the U.S. with the European approval expected soon (Tabs 2 and 3). The recommended daily dosage for salvage treatment is 400 mg bid given with food; for patients not tolerating solid food, a dosage of 200 mg four times a day (qid) is recommended, preferentially given with a nutritional supplement. Current data indicate no need for dosage adjustments based on differences in age, gender, race, renal or hepatic function [334]. The pharmacokinetics of posaconazole in pediatric patients (< 18 years of age) have not been adequately studied. Very limited data obtained in 12 pediatric subjects a 8 years of age appear to indicate no fundamental differences in trough plasma concentrations as compared to adults [346]. Salvage treatment with posaconazole resulted in successful outcomes in 5 of 11 pediatric subjects (8 to 17 years of age), which appears similar to the outcome in the adult population [347].

Echinocandin lipopeptides

The echinocandins are a distinct class of semisynthetic amphiphilic lipo-peptides that are composed of a cyclic hexapeptide core linked to a variably configured lipid side chain, and that act by inhibiting the synthesis of 1,3-p-D-glucan. This homo-polysaccharide is a major component of the cell wall of many pathogenic fungi and absent in mammalian cells. It provides osmotic stability and is important for cell growth and cell division. The first compound of this class undergoing preclinical evaluation was cilofungin (LY 121019), a semisynthetic echinocandin B derivative with activity limited to Candida spp. However, clinical development was abandoned in early stages due to toxicity concerns associated with the intravenous polyethylene glycol formulation vehicle [201]. Over the past decade, a second generation of semisynthetic echinocandins with extended antifungal spectrum against Candida and Aspergillus spp., a very favorable safety profile and pharmacokinetic characteristics has been developed: Anidulafungin (Eraxis™), caspofungin (Cancidas™), and micafungin (Mycamine™) (Fig. 3). The data accumulated thus far indicate that these agents are not fundamentally different with respect to spectrum, pharmacokinetics, safety and antifungal efficacy [201, 214].

Caspofungin

Caspofungin (Cancidas™) was the first licensed compound of the echino-candin class of antifungal agents. In vitro, caspofungin has broad-spectrum antifungal activity against Candida and Aspergillus spp. without cross-resistance to existing agents (Tab. 7). The compound exerts prolonged post antifungal effects and fungicidal activity against Candida species and causes severe damage to A. fumigatus at the sites of hyphal growth. Animal models have demonstrated efficacy against disseminated candidiasis and disseminated and pulmonary aspergillosis, both in normal and in immunocompro-mised animals [348].

Micafungin (FK463) Figure 3. Structural formulas of echinocandin lipopeptides.

Caspofungin is only available for IV administration. The compound exhibits dose-proportional plasma pharmacokinetics with a p half-life of approximately 15 h that allows for once daily dosing. It is highly (> 95%) protein bound and distributes into all major organ sites including the brain; however, concentrations in uninfected CSF are low. Caspofungin is metabolized by the liver following degradation and is slowly excreted into urine and feces; only small fractions (< 2%) of a dose are excreted into urine in unchanged form [348, 349] (Tab. 8). At the current dosage, caspofungin is generally well tolerated, and only a small fraction of patients enrolled on the various clinical trials (< 5%) discontinued therapy due to drug-related adverse events. The most frequently reported adverse effects include increased liver transaminases, gastrointestinal upset and headaches [350]. Because of transient elevations of hepatic transaminases in singledose interaction studies in healthy volunteers [348], the concomitant use of cyclosporine is currently not recommended; clinical experience, however, indicates that both drugs can be given concomitantly under careful monitoring [351-353]. Caspofungin has no significant potential for drug interactions mediated by the CYP450 enzyme system. It can reduce the AUC of tacrolimus by approximately 20% but has no effect on cyclosporine levels. Unspecific inducers of drug clearance and/or mixed inducer/inhibitors, namely efavirenz, nelfinavir, nevirapine, phenytoin, rifampin, dexametha-sone, and carbamazepine may reduce caspofungin concentrations [348].

The clinical efficacy of caspofungin against Candida spp. has been demonstrated first in Phase II and III studies in immunocompromised patients with esophageal candidiasis [354-356]. A multicenter, randomized, doubleblind Phase III clinical trial investigated the efficacy of caspofungin for primary treatment of invasive Candida infections in 224 mostly non-neutro-penic patients with amphotericin B deoxycholate (DAMB; 0.6-1.0 mg/kg) as comparator agent. Among patients receiving at least one dose of study drug, 73% of patients in the caspofungin cohort and 61.7% of patients in the DAMB cohort had a therapeutic success at the end of IV therapy. Among patients who received five or more doses, the response rates were 80.7% and 64.9%, respectively. There was no difference in relapse or survival, but caspofungin was better tolerated [357]. A multicenter Phase II salvage trial of caspofungin has been completed in 83 patients with definite or probable invasive aspergillosis refractory response or intolerant to standard therapies. As determined by an independent expert panel, a complete or partial response was observed in 45% of patients receiving at least one dose of caspofungin; in patients receiving the drug for > 7 days, the response rate was 56% [358]. Finally, in a large, randomized, double-blind clinical trial including 1095 patients, caspofungin was as effective as liposomal amphotericin B for empirical antifungal therapy in persistently febrile granulocytopenic patients but better tolerated. The proportion of patients who survived at least 7 days after therapy was greater in the caspofungin group (92.6% vs. 89.2%) [359].

Currently, caspofungin is licensed in the European Union and the United States in patients a 18 years of age for second line therapy of definite or probable invasive aspergillosis, for primary therapy in non-neutropenic patients with invasive Candida infections, and for empirical antifungal therapy in granulocytopenic patients with persistent fever (Tabs 2 and 3). The recommended dose regimen consists of a single 70-mg loading dose on day 1, followed by 50 mg daily thereafter, administered over 1 h. No dosage adjustment is required in patients with renal insufficiency. In patients with mild hepatic insufficiency (Child-Pugh category A), no adjustments are needed; in patients with moderate hepatic insufficiency (Child-Pugh category B), decreasing the maintenance dose to 35 mg/day is recommended after the loading dose of 70 mg. No recommendations exist for patients with severe hepatic insufficiency (Child-Pugh category C) [348].

In children and adolescents, the pharmacokinetics and safety of caspo-fungin was investigated using either a weight-based regimen (1 mg/kg body weight/day) or a body surface area regimen (50 mg/m2/day or 70 mg/m2/ day). Compared to adult patients treated with 50 mg/day, the dosage of 1 mg/kg/day achieved suboptimal exposure, whereas a dosage of 50 mg/m2/ day provided similar or slightly higher exposure relative to adults [360]. As a consequence, a dosage of 50 mg/m2/day has been selected for the further pediatric program. Although not approved in this population, caspofungin appears to be well-tolerated in pediatric patients: In a Phase I/II dose-finding study in 39 children and adolescents, none of the patients developed a serious drug-related adverse event or was discontinued for toxicity [360]. A similarly favorable safety profile has also been reported in immunocom-promised pediatric patients who received the compound for various indications, mostly in combination with other antifungal agents [353, 361], and in neonates with refractory invasive candidiasis [362-364].

Anidulafungin

The clinical efficacy of anidulafungin (Eraxis™) against Candida spp. has been demonstrated in Phase II or Phase III studies in immunocompro-mised patients with esophageal candidiasis and candidemia. Anidulafungin had equivalent efficacy to fluconazole in esophageal candidiasis in a randomized, double-blind, international multicenter study with success documented in 242/249 evaluable anidulafungin patients (97.2%) and 252/255 fluconazole patients (98.8%). Adverse events leading to discontinuation were reported in 29 anidulafungin patients (10%) versus 23 fluconazole patients (8%) [365]. Anidulafungin has also been investigated in patients with invasive candidiasis, including candidemia. In a dose-ranging study in 123 patients, success rates at the end of therapy were 84%, 90%, and 89% in the 50-, 75-, and 100-mg groups, respectively [366]. This study was followed by a randomized, double-blind Phase III study that compared anidulafungin (100 mg once daily) vs. fluconazole (400 mg once daily) in a total of 245 mostly non-neutropenic patients [367]. The preliminary data indicate that more patients receiving anidulafungin had a clinical and microbiological success at end of IV therapy (75.6% vs. 60.2%); similar superiority was found at the 2- and 6-week follow-ups after end of all therapy (64.6% vs. 49.2% and 55.9% vs. 44.1%, respectively). Survival at end of therapy was higher in the anidulafungin group (74% vs. 69%).

Anidulafungin is licensed in the U.S. for patients a 18 years of age for primary therapy of esophageal candidiasis and candidemia and select forms of invasive candidiasis in non-neutropenic subjects. The recommended dose regimen for esophagitis is 50 mg/day with 100 mg on day 1, and 100 mg/day with 200 mg on day 1 for candidemia. No dosage adjustment is needed in subjects with mild, moderate and severe renal impairment or in those undergoing hemodialysis. Mild to moderate hepatic impairment (Child-Pugh class A and B) does not cause clinically significant changes in the pharmacoki-netics of anidulafungin; dosage recommendations for subjects with severe hepatic impairment (Child-Pugh class C) are pending [368-370].

A pediatric Phase I/II multicenter study of the pharmacokinetics and safety of anidulafungin has been completed in 19 granulocytopenic children with cancer. Patients were divided into two age cohorts (2-11 and 12-17 years) and were enrolled into sequential groups to receive 0.75 or 1.5 mg/kg/ day. No drug-related serious adverse events were recorded. Pharmacokinetic parameters were similar across age groups and dosage cohorts and similar relative to adult subjects. Following single and multiple daily doses of 0.75 mg/kg and 1.5 mg/kg, plasma concentration data corresponded to those in adults following a daily 50 and 100 mg dose, respectively. Thus, in pediatric patients, anidulafungin can be dosed based on body weight [371].

Micafungin

Micafungin (Mycamine™) has been studied in open label dose-ranging studies of endoscopically proven esophageal candidiasis in HIV patients [372, 373]. A double-blind comparative study investigating 50, 100, 150 mg/day versus fluconazole 200 mg/day for HIV-associated esophageal candidiasis showed similar endoscopic cure rates and safety profiles for micafungin at doses of 100 and 150 mg/day and fluconazole [374]. A further randomized, double-blind comparative trial in 523 patients a 16 years with esophageal candidiasis investigated micafungin (150 mg/day) vs. fluconazole (200 mg/ day) [375]. For the primary end-point of endoscopic cure, treatment difference was -0.3% (micafungin 87.7%, fluconazole 88.0%). A large, Phase III, 1:1 randomized, double-blind non-inferiority trial has been completed that compared micafungin (100 mg/day) and liposomal amphotericin B (3 mg/ kg/day) for first-line therapy of invasive Candida infections in a total of 531 adult patients [376]. The overall success rate in both treatment arms was similar (89.6% vs. 89.5%). There was no difference in survival. Predefined safety parameters showed micafungin to have advantages over liposomal amphotericin B in renal function . The safety and efficacy of micafungin in combination with other antifungal agents for treatment of refractory asper-gillosis were investigated in a non-comparative multinational study in 85 patients with bone marrow transplantation. A complete or partial response was reported for 33 patients (39%) [377]. Micafungin (50 mg/day; 1 mg/kg for patients < 50 kg) versus fluconazole (400 mg/day; 8 mg/kg for patients

< 50 kg) has been investigated for prophylaxis of invasive fungal infections in 882 patients undergoing HSCT. Prophylaxis was given from the start of the conditioning regimen until 5 days following engraftment. The overall success rate was significantly higher for patients randomized to receive MIF (80.0% vs. 73.5%; p = 0.03). Drug-related adverse events were comparable [378].

Micafungin is licensed only in the U.S for treatment of esophageal can-didiasis and for prophylaxis against Candida infections in HSCT recipients. The recommended dose of micafungin for treating esophageal candidiasis is 150 mg/day; the dose of micafungin for prophylaxis of Candida infections in HSCT patients is 50 mg/day. Renal dysfunction (creatinine clearance

< 30 mL/min) or dialysis does not alter the pharmacokinetics of micafungin. Subjects with moderate hepatic dysfunction exhibited no differences in weight-normalized clearance [379].

Micafungin has been studied in 70 children and adolescents in an open label, sequential group, dose-escalation study of empirical therapy in febrile granulocytopenic children aged 2-17 years. In this study, micafungin was well tolerated at dosages ranging from 0.5 to 3.0 mg/kg/day; pharmacokinetics were linear and pharmacokinetic parameters were similar to those observed in adults [380]. Overall, more than 200 pediatric patients have been included up to now in clinical trials with micafungin and varying dosages and for varying indications without evidence for differences in safety and tolerance as compared to adults. A final pediatric dosage, however, has not been proposed.

Cure Your Yeast Infection For Good

Cure Your Yeast Infection For Good

The term vaginitis is one that is applied to any inflammation or infection of the vagina, and there are many different conditions that are categorized together under this ‘broad’ heading, including bacterial vaginosis, trichomoniasis and non-infectious vaginitis.

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