Intracellular concentrations of micafungin in different cellular compartments of the peripheral blood.

Whilst micafungin serum concentrations are well studied, little is known about its concentrations within cellular compartments of the peripheral blood. Hence, in this study blood samples were collected from patients receiving micafungin (n=26). These samples were separated by double-discontinuous Ficoll-Hypaque density gradient centrifugation. Intracellular concentrations within the obtained cells, i.e. peripheral blood mononuclear cells (PBMCs), polymorphonuclear leukocytes (PMNs) and red blood cells (RBCs), were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Within PBMCs and PMNs, the intracellular micafungin concentration was significantly increased compared with the concentration in plasma (P<0.001). The intracellular concentration within RBCs did not significantly differ from the plasma concentration. Micafungin reaches high concentrations in human PBMCs and PMNs and is present in RBCs. In vitro data showed that intracellular uptake of micafungin by PBMCs depends on the albumin concentration of the surrounding medium, but only at non-physiological protein concentrations.

Population pharmacokinetics of liposomal amphotericin B and caspofungin in allogeneic hematopoietic stem cell recipients.

Liposomal amphotericin B (LAMB) and caspofungin (CAS) are important antifungal agents in allogeneic hematopoietic stem cell transplant (aHSCT) recipients. Little is known, however, about the pharmacokinetics (PK) of both agents and their combination in this population. The PK of LAMB and CAS and the potential for PK interactions between both agents were investigated within a risk-stratified, randomized phase II clinical trial in 53 adult aHSCT recipients with granulocytopenia and refractory fever. Patients received either LAMB (n = 17; 3 mg/kg once a day [QD]), CAS (n = 19; 50 mg QD; day 1, 70 mg), or the combination of both (CAS-LAMB; n = 17) for a median duration of 10 to 13 days (range, 4 to 28 days) until defervescence and granulocyte recovery. PK sampling was performed on days 1 and 4. Drug concentrations in plasma (LAMB, 405 samples; CAS, 458 samples) were quantified by high-pressure liquid chromatography and were analyzed using population pharmacokinetic modeling. CAS concentration data best fitted a two-compartment model with a proportional error model and interindividual variability (IIV) for clearance (CL) and central volume of distribution (V(1)) (CL, 0.462 liter/h ± 25%; V(1), 8.33 liters ± 29%; intercompartmental clearance [Q], 1.25 liters/h; peripheral volume of distribution [V(2)], 3.59 liters). Concentration data for LAMB best fitted a two-compartment model with a proportional error model and IIV for all parameters (CL, 1.22 liters/h ± 64%; V(1), 19.2 liters ± 38%; Q, 2.18 liters/h ± 47%; V(2), 52.8 liters ± 84%). Internal model validation showed predictability and robustness of both models. None of the covariates tested (LAMB or CAS comedication, gender, body weight, age, body surface area, serum bilirubin, and creatinine clearance) further improved the models. In summary, the disposition of LAMB and CAS was best described by two-compartment models. Drug exposures in aHSCT patients were comparable to those in other populations, and no PK interactions were observed between the two compounds.

Higher clearance of micafungin in neonates compared with adults: role of age-dependent micafungin serum binding.

Micafungin, a new echinocandin antifungal agent, has been used widely for the treatment of various fungal infections in human populations. Micafungin is predominantly cleared by biliary excretion and it binds extensively to plasma proteins. Micafungin body weight-adjusted clearance is higher in neonates than in adults, but the mechanisms underlying this difference are not understood. Previous work had revealed the roles of sinusoidal uptake (Na(+) -taurocholate co-transporting peptide, NTCP; organic anion transporting polypeptide, OATP) as well as canalicular efflux (bile salt export pump, BSEP; breast cancer resistance protein, BCRP) transporters in micafungin hepatobiliary elimination. In the present study, the relative protein expression of hepatic transporters was compared between liver homogenates from neonates and adults. Also, the extent of micafungin binding to serum from neonates and adults was measured in vitro. The results indicate that relative expression levels of NTCP, OATP1B1/3, BSEP, BCRP and MRP3 were similar in neonates and in adults. However, the micafungin fraction unbound (f(u) ) in neonatal serum was about 8-fold higher than in the adult serum (0.033±0.012 versus 0.004±0.001, respectively). While there was no evidence for different intrinsic hepatobiliary clearance of micafungin between neonates and adults, our data suggest that age-dependent serum protein binding of micafungin is responsible for its higher clearance in neonates compared with adults.

Efficacy and safety of micafungin for treating febrile neutropenia in hematological malignancies.

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.

Micafungin does not influence the concentration of tacrolimus in patients after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Tacrolimus is commonly used in stem cell transplant recipients for prophylaxis of graft-vs-host disease. Micafungin is widely used as a strong antifungal agent in empirical therapy in patients with febrile neutropenia. Both tacrolimus and micafungin are substrates of cytochrome P450 3A4 in vitro. Therefore, there is risk of drug interaction with concomitant administration of these drugs. OBJECTIVE: To estimate the drug interaction of tacrolimus and micafungin by evaluating the pharmacokinetics in 6 patients who had undergone allogeneic stem cell transplantation. RESULTS: The mean (SD) concentration-dose ratio of tacrolimus in all patients at 1, 4, 8, and 24 hours after concomitant administration of micafungin was 607 ± 306, 653 ± 328, 699 ± 340 and 671 ± 403 (ng/mL)/(mg/kg/d), respectively, and without micafungin was 756 ± 314 (ng/mL)/(mg/kg/d). The percentage of the concentration-dose ratio in patients treated with tacrolimus and micafungin vs patients treated with tacrolimus alone was 98%, 105%, 112%, and 108% at 1, 4, 8, and 24 hours, respectively. For both tacrolimus and micafungin, the 90% confidence intervals for the primary pharmacokinetic parameters (ie, the concentration-dose ratio at each point) ranged from 80% to 125%. CONCLUSION: We conclude that there is no drug interaction between tacrolimus and concomitantly administered micafungin in stem cell transplantation recipients.

Alternate-day micafungin antifungal prophylaxis in pediatric patients undergoing hematopoietic stem cell transplantation: a pharmacokinetic study.

Disseminated fungal infection is a major cause of morbidity and mortality in children undergoing hematopoietic stem cell transplantation (HSCT). Prophylaxis with amphotericin B can be limited by renal toxicity. Oral triazoles can be limited by poor absorption, large interindividual pharmacokinetic (PK) variability, and hepatic toxicity, leading to interruptions in therapy and breakthrough infections. Intravenous (i.v.) micafungin has potential advantages, because of its better safety profile, specifically in terms of hepatic and renal toxicity, and lack of drug-drug interactions with common medications used in the HSCT setting. We hypothesized that higher dose micafungin (3 mg/kg) every other day will provide drug exposure similar to standard dosing (1 mg/kg) given daily, and improve patient compliance in very young children in whom oral medications can be challenging, at reduced administration costs. Both animal and adult patient data support the use of this approach. Fifteen children (M/F = 11/4, aged < or =10 years; mean: 3.9 years, range: 0.6-10 years) with various hematologic, metabolic, and immune deficiency disorders undergoing HSCT received a single dose of micafungin (3 mg/kg) i.v. over 1 hour. Dose selection was based on published PK data in pediatric patients, and exploration of different dosing regimens using Monte Carlo PK/PD simulation. Blood samples were drawn around this dose and PK analysis was conducted using standard noncompartmental methods. Micafungin at 3 mg/kg dose was well tolerated in all patients. Measurable plasma concentrations were present in all cases at 48 hours. Half-life and clearance observed were comparable to previous pediatric PK data, with clearance being higher than adults as expected. Volume of distribution was higher in our patients compared to published pediatric data, likely because of a larger proportion of very young children in our study cohort. After correction for protein binding, concentrations at the end of the dosing interval during maintenance treatment remain above the minimum inhibitory concentration (MIC) of highly susceptible fungal pathogens. These data suggest that alternate day micafungin dosing, as described here, may provide an attractive alternative for antifungal prophylaxis in HSCT patients and merits further evaluation.

Intrapulmonary pharmacokinetics and pharmacodynamics of micafungin in adult lung transplant patients.

Invasive pulmonary aspergillosis is a life-threatening infection in lung transplant recipients; however, no studies of the pharmacokinetics and pharmacodynamics (PKPD) of echinocandins in transplanted lungs have been reported. We conducted a single-dose prospective study of the intrapulmonary and plasma PKPD of 150 mg of micafungin administered intravenously in 20 adult lung transplant recipients. Epithelial lining fluid (ELF) and alveolar cell (AC) samples were obtained via bronchoalveolar lavage performed 3, 5, 8, 18, or 24 h after initiation of infusion. Micafungin concentrations in plasma, ELF, and ACs were determined using high-pressure liquid chromatography. Noncompartmental methods, population analysis, and multiple-dose simulations were used to calculate PKPD parameters. Cmax in plasma, ELF, and ACs was 4.93, 1.38, and 17.41 microg/ml, respectively. The elimination half-life in plasma was 12.1 h. Elevated concentrations in ELF and ACs were sustained during the 24-h sampling period, indicating prolonged compartmental half-lives. The mean micafungin concentration exceeded the MIC90 of Aspergillus fumigatus (0.0156 microg/ml) in plasma (total and free), ELF, and ACs throughout the dosing interval. The area under the time-concentration curve from 0 to 24 h (AUC0-24)/MIC90 ratios in plasma, ELF, and ACs were 5,077, 923.1, and 13,340, respectively. Multiple-dose simulations demonstrated that ELF and AC concentrations of micafungin would continue to increase during 14 days of administration. We conclude that a single 150-mg intravenous dose of micafungin resulted in plasma, ELF, and AC concentrations that exceeded the MIC90 of A. fumigatus for 24 h and that these concentrations would continue to increase during 14 days of administration, supporting its potential activity for prevention and early treatment of pulmonary aspergillosis.

Bronchopulmonary disposition of micafungin in healthy adult volunteers.

By way of bronchoscopy and bronchoalveolar lavage, intrapulmonary steady-state concentrations of micafungin administered at 150 mg daily to 15 healthy volunteers were determined at 4, 12, and 24 h after the third dose. The micafungin disposition was predominantly intracellular, with approximately 106% penetration into alveolar macrophages and 5% penetration into epithelial lining fluid.

Effect of liver and kidney function on migafungin disposition in patients with hematologic malignancies.

The plasma concentration of micafungin (MCFG) after intravenous infusion of MCFG at 150 or 300 mg/day over 1 hour to 49 patients with hematologic malignancies were determined, and the relationship between the plasma concentrations and the patients' laboratory parameters of liver and kidney function was analyzed. Plasma samples were obtained at the end of the initial administration of MCFG, 5 to 6 hours after the start of the initial administration, immediately before the second dosing, immediately before the fourth dosing, and the end of the fourth dosing. The plasma concentration of MCFG was measured by high performance liquid chromatography. The plasma concentration of MCFG was correlated with the doses of MCFG per kilogram body weight. The peak concentration after the initial administration was 3.8 times higher than the trough level after the initial administration. The steady-state peak and trough levels were 1.4-1.5 times higher than those after the initial administration. There was no correlation between the laboratory parameters of liver/kidney function and the dose-normalized plasma concentration of MCFG. These results suggest that MCFG can be administered safely to patients with liver or kidney dysfunction without adjusting the dose.