104 A.H. Groll et al.
adults. If caspofungin is co-administered with the listed inducers of drug clearance, a dose of 70 mg/m2 daily (maxi- mum daily dose of 70 mg) should be considered [145, 146].
Approval Status and Dosing Recommendations
In USA, caspofungin is licensed in adults and pediatric patients 3 months and older for treatment of esophageal can- didiasis, candidemia, certain forms of invasive Candida infections, including intra-abdominal abscesses, peritonitis and pleural space infections. It is recommenrded as second line therapy of proven or probable invasive aspergillosis and for empirical antifungal therapy in granulocytopenic patients with persistent fever [145]. In Europe, the compound is approved in adult and pediatric patients of all ages for treat- ment of invasive candidiasis, second line treatment of inva- sive aspergillosis, and for empirical therapy for presumed fungal infections in neutropenic patients [146].
The recommended dose regimen for adults consists of a single 70-mg loading dose on day 1, followed by 50 mg daily thereafter, administered over 1 h. The regimen approved in pediatric patients 3 months to 17 years is 50 mg/m2 daily after a 70 mg/m2 loading dose (maximum daily dose 70 mg).
The preliminary dosage in infants < 3 months and in prema- ture neonates is 25 mg/m2 daily. 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 main- tenance dose to 35 mg/day is recommeded after the loading dose of 70 mg. No recommendations exist for patients with severe hepatic insufficiency (Child-Pugh category C).
Caspofungin has been shown to cross the placental barrier and to be embryotoxic in rats and rabbits. Adequate data in pregnant and lactating women do not exist, and the com- pound should only be used if the potential benefit justifies the risk to the fetus [145, 146].
105 Echinocandins
(Table 5) [160, 163] and were selected for the further pediatric development. Current pharmacokinetic data in premature neonates indicate a considerably higher cler- ance rate than in other pediatric age groups and adults and the potential need for larger doses in these infants [161, 164–166].
Clinical Efficacy
The antifungal efficacy and the dose-response relationship of micafungin against human Candida infections were investi- gated in a series of phase II and III clinical trials in mostly HIV-infected patients with esophageal candidiasis [167–
169]. In a randomized, double-blind clinical trial including a total of 245 patients ³ 18 years with HIV-infection and esoph- ageal candidiasis, the endoscopic cure rate was dose-depen- dent with 68.8%, 77.4%, and 89.8%, respectively, following 50, 100, and 150 mg of micafungin. The endoscopic cure rate for 100 and 150 mg of micafungin combined (83.5%) was comparable to that of fluconazole (86.7%) [169]. In a further randomized, double-blind comparative trial con- ducted in a total of 523 patients ³ 16 years with esophageal candidiasis, micafungin (150 mg) was as effective as flucon- azole (200 mg daily) with endoscopic cure rates of 87.7%
versus 88.0%, and recurrence rates at 4-weeks post-treatment were not different [169].
The efficacy of micafungin as first line therapy of inva- sive Candida infections has been established through two large randomized, double-blind phase III clinical trials [126, 170]. The first trial compared micafungin 100 mg daily to liposomal amphotericin B 3 mg/kg daily in a total of 531 adult patients. Treatment success was defined as clinical response combined with mycological response at end of therapy. Candidemia constituted approximately 85% of the cases, and non-albicans infections comprised approximately 60% of cases. Most patients (88%) were non-neutropenic. The overall success rate in both treat- ment arms was similar – 74% of those receiving mica- fungin and 70% in those receiving liposomal amphotericin B, and there was no difference in survival [170]. The sec- ond trial compared micafungin 100 mg daily and mica- fungin 150 mg daily to the standard dosage of caspofungin, 50 mg daily, in a total of 595 mostly non-neutropenic (92%) adults with candidemia and other forms of invasive candidiasis. At the end of blinded intravenous therapy, treatment was considered successful for 76.4% of patients in the micafungin 100 mg group, 71.4% in the micafungin 150 mg group, and 72.3% in the caspofungin group. There were no significant differences in time to culture negativ- ity, mortality, relapses and emerging infections among the study arms [126]. The clinical efficacy of micafungin
against invasive candidiasis is further supported by an open label, non-comparative trial in 126 patients with new or refractory candidemia who received the drug alone or in combination with another agent. Complete or partial responses were observed in 83.3% patients overall with- out apparent species-related differences [171].
A multi-national, non-comparative open-label clinical trial investigated micafungin for proven or probable invasive aspergillosis alone or in combination with another systemic antifungal agent in 225 patients. A favorable response rate at the end of therapy was seen in 35.6%. Of those treated only with micafungin, favorable responses were seen in 6/12 of the primary and 9/22 of the salvage therapy group. Most patients were treated with one or two other drugs as well as micafungin, and the overall response rate for those patients was 34% [172]. In the subgroup of 98 hematopoietic stem cell transplant recipients, a partial or complete response was seen in 3 of 8 patients who were treated with micafungin alone [173].
Micafungin was also compared with fluconazole for pro- phylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplanta- tion. In a randomized, double-blind, multi-institutional, phase III trial involving 882 adult and pediatric patients, patients received either 50 mg of micafungin (1 mg/kg for
<50 kg body weight) or 400 mg of fluconazole (8 mg/kg for
<50 kg) daily. Success was defined as the absence of sus- pected, proven, or probable invasive fungal infection (IFI) through the end of therapy and as the absence of proven or probable IFI through the end of the 4-week period after treat- ment. The overall efficacy of micafungin was superior to that of fluconazole as antifungal prophylaxis (80.0% vs. 73.5%, p = .03), thus demonstrating efficacy of micafungin for anti- fungal prophylaxis in neutropenic patients [174] A further, smaller randomized trial in 106 adult HSCT patients com- pared prophylaxis with micafungin 150 mg to fluconazole 400 mg. Success, defined the same as noted above, was 94%
in the micafungin-treated patients ans 88% in the fluconazole recipients [175].
In pediatric patients, efficacy data from substudies of two large randomized comparative trials have been reported [174, 176]. In patients undergoing stem cell transplantation, prophylaxis with micafungin was as effective as prophylaxis with fluconazole without signals for differences in compari- son to the entire study population [174]. Similar observa- tions were made in 98 pediatric patients with invasive candidiasis or candidemia, 57 of whom were <2 years old and 19 who were premature neonates. Treatment success was observed for 35/48 (72.9%) patients treated with mica- fungin and 38/50 (76.0%) patients treated with liposomal amphotericin B. Efficacy findings were independent of neu- tropenia status, age, and whether the patient was premature at birth [176].
106 A.H. Groll et al.
Safety and Tolerance
In dose-ranging studies in immunocompromised adult patients, micafungin was well tolerated during chronic dosing at dos- ages up to 200 mg or 8 mg/kg daily without reaching a maxi- mum tolerated dose [156, 168, 177]. A pooled analysis from 17 clinical efficacy and safety studies with micafungin, includ- ing 3,028 mostly immunocompromised patients who received at least one single dose of micafungin, has been reported. The mean age of patients was 41.4 years with 296 (9.8%) children
<16 years and 387 (12.8%) older patients ³ 65 years. The median micafungin daily dose was 100 mg for adult patients and 1.5 mg/kg for children. The mean duration of exposure was 18 and 29 days, respectively. The most frequently reported treatment-related adverse events (³ 2%) were nausea, vomit- ing, phlebitis, hypokalemia, fever, and diarrhea. Increases in liver enzymes occurred in about 2% of patients (2.0%) [178].
In the pivotal comparative studies, micafungin had a similar safety profile compared to fluconazole and caspofungin and was better tolerated than liposomal amphotericin B; less than 5% of patients discontinued treatment with micafungin related to adverse events [126, 168, 170, 174].
Clinical trials in pediatric patients revealed no differences in safety as compared to adults [163, 174, 176]. In premature neonates, micafungin has been tolerated without limiting toxicity or higher rates of adverse events at multiple doses of up to 15 mg/kg daily [165, 166].
Because of the observation of foci of altered hepatocytes and hepatocellular tumors after long-term exposure studies in rats, the European Summary of Product Characteristics recommends careful monitoring of liver function values dur- ing micafungin treatment and early discontinuation in the presence of significant and persistent elevation of liver transaminases, and also recommends a careful risk/benefit evaluation, particularly in patients having severe liver func- tion impairment, chronic liver diseases or receiving concom- itant hepatotoxic therapy [179]. The clinical relevance of these observed preclinical findings, however, is unknown.
Drug Interactions
Studies using human liver microsomes revealed neither inhibition nor stimulation of CYP1A2, CYP2D6, CYP2E1, CYP2C9, and CYP2C19 but inhibition of CYP3A4 in a manner comparable to fluconazole [180–182]. However, studies in healthy volunteers revealed no drug interaction between mica- fungin and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, rifampicin, itraconazole, voriconazole and amphotericin B. In these studies, no evidence of altered pharmacokinetics of
micafungin was observed. Exposure (AUC) of itraconazole, sirolimus, and nifedipine was slightly increased in the pres- ence of micafungin. Patients receiving sirolimus, nifedipine or itraconazole in combination with micafungin should be moni- tored for toxicity due to these agents and the dosage of siroli- mus, nifedipine or itraconazole should be reduced, if necessary [10, 179, 183–185].
Approval Status and Dosing Recommendations
In USA, micafungin is licensed in adults for treatment of esoph- ageal candidiasis, candidemia, acute disseminated candidiasis, Candida peritonitis and abscesses, and as prophylaxis against Candida infections in patients undergoing hematopoietic stem cell transplantation [183]. In Europe, micafungin is approved for treatment of esophageal candidiasis in patients ³ 16 years of age for whom intravenous therapy is appropriate, for treatment of invasive candidiasis in all age groups, and for prophylaxis of Candida infection in patients undergoing allogeneic hematopoi- etic stem cell transplantation or patients who are expected to have neutropenia for >10 days [179].
The recommended dosage regimens approved by both the FDA and the EMEA for adults is 150 mg for esophageal can- didiasis,100 mg for invasive candidiasis, and 50 mg for pro- phylaxis of Candida infections, administered once daily over 1 h. The corresponding regimens approved by the EMEA in pediatric patients £ 40 kg of body weight are 3, 2, and 1 mg/kg, respectively. In patients with invasive candidiasis, the option of dose escalation to 200 mg or 4 mg/kg, respectively, in patients with persistent clinical or microbiological findings is offered [179, 183].
No dosage adjustments are required based on race, gen- der, in patients with renal insufficiency, or in patients with mild to moderate hepatic insufficiency (Child-Pugh category A and B). No recommendations exist for patients with severe hepatic insufficiency (Child-Pugh category C).
Micafungin has been shown to cross the placental barrier and to be embryotoxic in laboratory animals. Adequate data in pregnant and lactating women do not exist, and the com- pound should only be used if the potential benefit justifies the risk to the fetus [179, 183].
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