The Impact of Total Bilirubin on Plasma Micafungin Levels in Living-Donor Liver Transplantation Recipients with Severe Liver Dysfunction

Abstract

Mcafungin (MCFG) is a semisynthetic antifungal echinocandin-like lipopeptide that inhibits the synthesis of 1,3-b-D-glucan, an essential polymeric polysaccharide in the cell wall of many pathogenic fungi.1,2) MCFG has superior antibacterial activity against Candida and Aspergillus species.3) Currently, this agent is commonly administered to prevent and treat deep-seated mycosis in patients with various diseases. [4][5][6][7][8] It is also administered to recipients of living-donor liver transplantations (LDLT) to prevent or treat invasive fungal infections. MCFG is metabolized primarily by sulfatase and cytochrome P450, and has low hepatic extraction ratio. Additionally, MCFG has very high protein binding (Ͼ99.5%) in plasma and 90% of MCFG administered and its metabolites are eliminated through the bile. 9)It is reported that MCFG has low mechanism-based toxicity because the inhibition of fungal cell wall synthesis effected by echinocandins has no relevance for mammalian cells.10,11) MCFG was reported to be well tolerated at doses from 2.5 to 150 mg/d in healthy male volunteers, suggesting that MCFG could be administered safely to most patients. 6)Furthermore, other reports have concluded that dose adjustment is not required for elderly patients or patients with moderate liver dysfunction or severe renal dysfunction. 9,12) However, little is known about the pharmacokinetic or pharmacodynamic changes of MCFG in LDLT-recipients with extremely unstable liver function. In the present study, we measured the plasma concentration of MCFG in 20 recipients of LDLT and evaluated the clinical effects and safety of MCFG using biochemical parameters. MATERIALS AND METHODS PatientsThe subjects in this study were 20 patients who visited the Department of Hepatobiliary Pancreatic Surgery of Mie University Hospital between April 2003 and March 2007. After receiving a LDLT, these patients were diagnosed with fungal infections according to a rise in b-D-glucan (BDG) or a positive reaction to an Aspergillus antigen. Written informed consent was obtained for this study from all subjects or their families. In addition, the Ethics Committee of our university gave its approval for this study. MCFG Infusion and Blood SamplingThe subjects received MCFG as treatment for their fungal infections. MCFG was administered by a constant infusion for 60 min via a peripheral venous catheter, once daily, at doses of 100-300 mg. When the blood MCFG concentration reached a steady state, the patient's blood samples were taken before (trough) and an hour after (peak) the drip infusion of MCFG. The blood was centrifuged at 2100ϫg for 20 min at room temperature, and the plasma was separated and kept at Ϫ80°C until analysis.Determination of Plasma Micafungin MCFG solution (100 mg/ml) and FR195743 solution (internal standard (IS); 100 mg/ml) were donated by Astellas Pharma Inc. (Tokyo). All other reagents were of the highest grade available. The plasma concentrations of MCFG were determined by high performance liquid chromatography (HPLC) according to the ...

Impact of special patient populations on the pharmacokinetics of echinocandins

“…For patients with both moderate and severe hepatic impairment, the differences in exposure was not considered clinically relevant, as a consequence no dose adjustments are advised for patients with any grade of hepatic impairment [84,95]. In accordance, in living donor liver transplant recipients, micafungin PK was comparable with healthy subjects [96][97][98]. The latter result was striking as another study demonstrated that higher bilirubin levels correlated with higher concentration/ dose ratios [97].…”

Low but Sufficient Anidulafungin Exposure in Critically Ill Patients

“…Multiple linear regression analysis was performed using a backward elimination strategy, keeping variables with P values of Ͻ0.1 in the model. The variables that were included in the multiple linear regression analysis were gender (11), age (11), total body water (11), albumin (13), total bilirubin (30,31), and the disease severity score with the lowest P value for the correlation.…”

Determination of micafungin and anidulafungin in human plasma: UV- or mass spectrometric quantification?

“…Generally, no dosage adjustments are required in patients with varying degrees of hepatic or renal impairment [4,5]. However, clinical data suggest that dose adjustments are needed for special subgroups of patients, such as infants [6], patients with severe liver dysfunction [7] or overweight or obese patients [8] to achieve effective systemic drug concentrations. Optimized drug concentrations have to avoid levels lower than the minimum inhibitory concentration (MIC) of the pathogen, as well as to high concentrations because of the socalled "Eagle effect".…”

“…In the literature, some HPLC-fluorescence methods for the quantitative determination of micafungin in plasma were reported [7,[11][12][13][14][15][16]. The simultaneous detection of two active metabolites of micafungin was also described [15,16].…”

“…Either the I.S. 's had no structural similarity to the analyte [2,21] or were custom synthesized analogs, which were not commercially available [4,7,[12][13][14][15][17][18][19][20]. This makes it difficult to establish such a method outside a dedicated clinical study.…”