micafungin and Liver-Diseases

Currently, three echinocandins are available for the treatment of fungal infections. Micafungin is the latest drug to be incorporated into this group of antifungal agents. Although the mechanism of action of micafungin is similar to that of other echinocandins, this molecule has certain pharmacokinetic characteristics that distinguish it from other drugs in this group. Nowadays, there is wide information on the pharmacokinetic behavior of micafungin, mainly from patients included in clinical trials. However, there is far less knowledge of the pharmacokinetics of this echinocandin in special populations. The aim of the current review was to analyze the available information on the pharmacokinetics of micafungin in pediatric patients, the elderly, patients with renal insufficiency or liver failure, and transplant recipient.

Topics: Adolescent; Adult; Age Factors; Aged; Antifungal Agents; Child; Child, Preschool; Clinical Trials as Topic; Comorbidity; Cytochrome P-450 CYP3A; Drug Interactions; Echinocandins; Humans; Infant; Kidney Diseases; Lipopeptides; Liver Diseases; Micafungin; Middle Aged; Mycoses; Postoperative Complications; Transplantation; Young Adult

Less toxic antifungal drugs are required for empirical antifungal therapy. Micafungin is an echinocandin drug that is effective against both Candida and Aspergillus, and preliminary clinical studies have shown good antifungal activity. We prospectively examined the effect and safety of micafungin against febrile neutropenia with suspected fungal infection in 53 patients (median age, 56 years) who had undergone chemotherapy. The administered dose of micafungin was 150 mg/day, and its effect was evaluated as fever resolution as well as the results of chest imaging and serum fungal tests. Micafungin levels were measured on day 4 after the first administration using high-performance liquid chromatography. We also measured trough levels of micafungin. Underlying diseases comprised acute lymphoblastic leukemia (n = 4), acute myeloid leukemia (n = 20), multiple myeloma (n = 3), and non-Hodgkin's lymphoma (n = 26). The overall efficacy of micafungin was 70%. Breakthrough fungal infections were documented in two (3.8%) patients, both of whom died of invasive mycosis. None of the patients were switched to other antifungal drugs due to events unrelated to adverse effects. Plasma levels of micafungin and the degree of hepatic or renal dysfunction did not correlate. Micafungin is safe and effective for the empirical antifungal therapy of febrile neutropenia in patients with hematological malignancies.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Antineoplastic Agents; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Echinocandins; Female; Fever; Hematologic Neoplasms; Humans; Kidney Diseases; Lipopeptides; Liver Diseases; Male; Micafungin; Middle Aged; Mycoses; Neutropenia; Treatment Outcome

The clinical efficacy of micafungin (MCFG) in surgery, emergency, and intensive-care medicine has been studied in only a limited number of cases. We conducted a multicenter postmarketing study to evaluate MCFG efficacy and safety in Japan. MCFG was given to patients with a temperature exceeding 37.5 degrees C, either with a proven fungal infection based on mycological or histopathological examination, or those who were regarded as having probable or possible fungal infections (patients who had at least one high-risk factor for the development of a systemic fungal infection and for whom fungi had been detected at multiple sites by surveillance culture or a positive beta-D-glucan test). Efficacy was evaluated using the AKOTT algorithm created by our group (AKOTT is an acronym created from the first letter of the surname of each of the five members of the evaluation committee). Of the 180 patients enrolled, 68 were excluded by exclusion criteria or for other reasons, and 112 (58 with proven candidiasis, 1 with proven aspergillosis, and 53 with suspected fungal infection) were evaluated for efficacy. MCFG was administered at a mean daily dose of 104 mg for a mean duration of 14.2 days. It was effective in 72 p 72 patients, ineffective in 28, and the effect was undeterminable in 12, for an overall clinical efficacy 72.0%. MCFG was effective in 78.6% of those with proven candidiasis and in 65.1% with suspected fungal infection, but it was ineffective in the 1 patient with aspergillosis. MCFG eradicated 77.6% (52/67) of fungi isolated. There were 69 drug-related adverse reactions, mainly abnormal hepatic function tests, in 37 of 178 patients evaluated for safety. One adverse reaction, skin eruption, had a probable causal relationship with drug treatment. In conclusion, MCFG had high clinical efficacy and safety in the treatment of deep-seated fungal infections in surgery, emergency, and intensive-care medicine, indicating good potential as a firstline drug for both targeted and empirical therapies.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Algorithms; Antifungal Agents; Aspergillosis; Candidiasis; Child; Child, Preschool; Drug Eruptions; Echinocandins; Emergency Service, Hospital; Female; Humans; Intensive Care Units; Japan; Lipopeptides; Liver Diseases; Male; Micafungin; Middle Aged; Postoperative Complications; Product Surveillance, Postmarketing; Treatment Outcome

Micafungin is an antifungal agent metabolized by arylsulfatase with secondary metabolism by catechol-O-methyltransferase. The objectives of this study were to estimate the pharmacokinetic parameters and plasma protein binding of micafungin in volunteers with moderate hepatic dysfunction (n = 8), volunteers with creatinine clearance < 30 mL/min (n = 9), and matched controls (n = 8 and n = 9, respectively). Single-dose micafungin pharmacokinetics were estimated using noncompartmental techniques. There was a statistically lower area under the observed micafungin concentration-time curve (AUC) from time 0 to infinity for subjects with moderate hepatic dysfunction as compared to control subjects (97.5 +/- 19 microg.h/mL vs 125.9 +/- 26.4 microg.h/mL, P = .03), although there was no difference in micafungin weight-adjusted clearance (10.9 +/- 1.7 mL/h/kg vs 9.8 +/- 1.8 mL/h/kg, P = .2). The difference in area under the concentration-time curve may be explained by the differences in body weight between subjects and controls. Renal dysfunction did not alter micafungin pharmacokinetics.

Topics: Adult; Area Under Curve; Echinocandins; Female; Humans; Infusions, Intravenous; Kidney Diseases; Lipopeptides; Lipoproteins; Liver Diseases; Male; Metabolic Clearance Rate; Micafungin; Middle Aged; Peptides, Cyclic

In this prospective observational study performed in 12 hospitalized patients with proven or suspected invasive fungal infection treated for a mean of 14 days with micafungin (MCF), 8 of whom with pre-existing liver function impairment, plasma levels of MCF at steady state were not correlated with liver function tests at the beginning of treatment. Liver function remained stable or even improved in all patients, except in one in which MCF was discontinued due to liver toxicity.

Topics: Antifungal Agents; Echinocandins; Female; Humans; Invasive Fungal Infections; Lipopeptides; Liver Diseases; Male; Micafungin; Middle Aged; Prospective Studies

Micafungin is an echinocandin with potent activity against a broad range of fungal species, including Candida species. The pharmacokinetic and safety profiles of micafungin have been evaluated in individuals with mild-to-moderate hepatic dysfunction, but not in individuals with severe hepatic dysfunction. Therefore, the present study assessed the pharmacokinetics and safety of a single 100 mg dose of micafungin in healthy subjects (n = 8) and subjects with severe hepatic dysfunction (n = 8). Mean maximum plasma concentration of micafungin and mean area under the plasma micafungin concentration-time curve extrapolated to infinity were lower in subjects with severe hepatic dysfunction (7.3 ± 2.4 µg/mL and 100.1 ± 34.5 h·μg/mL, respectively) than in subjects with normal hepatic function (10.3 ± 2.5 µg/mL and 142.4 ± 28.9 h·μg/mL, respectively). Mean clearance was higher in subjects with severe hepatic dysfunction (1,098 ± 347 mL/h) than in subjects with normal hepatic function (728 ± 149 mL/h). Concentrations of albumin in subjects with severe hepatic dysfunction were lower. Assessments of micafungin plasma protein binding suggested that the higher clearance in subjects with severe hepatic dysfunction may be due to higher unbound concentrations. However, the magnitude of the differences was not considered clinically meaningful and is comparable with exposures reported elsewhere for a 100-mg dose in patients treated for invasive candidiasis. Thus, dose adjustment in subjects with severe hepatic dysfunction is not warranted. Micafungin was well tolerated in all subjects throughout the study.

Topics: Area Under Curve; Case-Control Studies; Echinocandins; Female; Humans; Lipopeptides; Liver; Liver Diseases; Male; Micafungin; Middle Aged

The objective of this study was to propose a clinically effective and safe micafungin (MCFG) treatment for 20 recipients of living-donor liver transplantations (LDLTs), after considering the influence of liver function on its plasma pharmacokinetics. In all patients, an improvement of clinical symptoms was observed after MCFG treatment. Liver and renal functions were not significantly changed by the administration of MCFG. In the recipients, the trough plasma concentration of MCFG was 4.6+/-2.1 [corrected] microg/ml (mean+/-S.D.), which was dependent on the dose (p=0.0033). Additionally, there was a good correlation between the trough and peak MCFG plasma concentrations (p<0.0001). The trough concentration of MCFG was significantly correlated with serum total bilirubin levels (p=0.0166). In addition, the MCFG concentration/dose (C/D) ratio was significantly higher in the patients with total bilirubin levels >5 mg/dl than in those with total bilirubin levels < or =5 mg/dl (p<0.0001). The C/D ratio of MCFG was weakly but not significantly correlated with total bilirubin levels at total bilirubin levels >5 mg/dl (p=0.0508). Therefore, a reduced dose of MCFG should be considered when total bilirubin levels are >5 mg/dl. Furthermore, careful monitoring of total bilirubin levels is recommended during MCFG treatment in LDLT-recipients with severe liver dysfunction. These results provide helpful advice about MCFG administration for the treatment of fungal infections in LDLT patients with fluctuating liver function.

Topics: Antifungal Agents; Bilirubin; Drug Monitoring; Echinocandins; Female; Humans; Hyperbilirubinemia; Lipopeptides; Liver Diseases; Liver Function Tests; Liver Transplantation; Living Donors; Male; Micafungin; Middle Aged