Analysis of the Blood Level of Micafungin Involving Patients with Hematological Diseases: New Findings Regarding Combination Therapy with Tacrolimus

Abstract

The action mechanism of a new candin antifungal agent, micafungin (MCFG), which was developed as the sixth antifungal agent in Japan, differs from that of conventional antifungal agents, and this agent may be clinically useful. MCFG has a broad spectrum against Candida and Aspergillus in vitro by inhibiting the biosynthesis of the main constituent comprising the fungal cellular wall, 1,3-b-D glucan.1,2) As this agent shows favorable lung transfer, 3) it may be useful for preventing and treating pulmonary mycosis.We previously reported the efficacy of this agent and the incidence of side effects in 17 patients with hematological diseases to whom MCFG was administered to treat/prevent pulmonary aspergillosis. 4) Our study suggested that 150 mg or more of MCFG is required to treat/prevent pulmonary aspergillosis; however, the necessity of adjusting the dose in patients with liver/kidney hypofunction and the presence or absence of interactions with other agents remain to be clarified. As an immunosuppressive agent, tacrolimus , is administered to patients after hematopoietic stem cells transplantation from non-relatives for a long period, it should be confirmed whether interactions related to combination therapy with MCFG appear.In this study, we measured the blood level of MCFG in 29 patients with hematological diseases, and analyzed the data. We report findings regarding administration to patients with liver/kidney hypofunction and combination therapy with FK-506. MATERIALS AND METHODS SubjectsThe subjects were 29 patients who were admitted to the First Department of Internal Medicine (Department of Hematology) in Nagano Red Cross Hospital between February 2003 and October 2004. Written informed consent regarding the measurement of the blood MCFG level was obtained from the patients or their families. As a rule, blood was collected 3 d or more after the start of administration, when MCFG reached a steady state, to obtain a trough value. If necessary, blood was collected in accordance with the general condition.Informed Consent In obtaining informed consent from the patients or their families, we paid attention to protect the patients' rights according to the Helsinki declaration. In addition, it was explained that blood samples were not used for purposes other than this study. The Ethics Committee in our hospital approved this study.Preparation of the Solutions A standard solution of MCFG and a solution containing an internal standard substance (IS), FR195743, were supplied by Fujisawa Pharmaceutical Co., Ltd. MCFG was dissolved in ethanol at a concentration of 100 mg/ml, and the standard stock solution thus prepared was stored at Ϫ20°C. The IS was dissolved in 0.02 mol/l potassium dihydogenphosphate/acetonitrile (50/50, v/v) at a concentration of 100 mg/ml, and the IS stock solution thus prepared was stored at 4°C. The standard stock solution was diluted with ethanol to make standard working solutions at a concentration of 25, 10, 2.5, 1, 0.25, and 0.05 mg/ml, respectively. The IS stock solution was diluted with ...

Change of the Blood Concentration of Tacrolimus after the Switch from Fluconazole to Voriconazole in Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation

“…The C/D ratios of FK506 was positively correlated with T.Bil (r 2 ϭ0.782, pϭ0.0003, Fig. 2B), whereas not with creatinine clearance (CCr) as a renal function parameter 20) for convenience (data not shown). In other two subjects, there was no correlation between C/D ratios of FK506 and CCr, or T.Bil in each group throughout the investigation period (data not shown).…”

“…2A). The blood total bilirubin value (T.Bil) representatively substituted as liver function parameter 20) for convenience was increased in this subject ( Table 1). The C/D ratios of FK506 was positively correlated with T.Bil (r 2 ϭ0.782, pϭ0.0003, Fig.…”

“…Assessment The blood concentrations of FK506 were normalized for the daily dose of FK506 (ng/ml per mg/kg) 11,14,20) ; that is, the concentration/dose (C/D) ratio was used to assess the impact by switching co-administered triazole antifungal agent from FCZ to VCZ on the blood concentration of FK506. The following values were excluded from this assessment as FK506 was discontinued for high concentration, because the daily dose of FK506 was unknown.…”

New antifungal agents for the treatment of candidaemia

“…By contrast, no changes were observed in plasma levels of other drugs such as tacrolimus, mycophenolate, ciclosporin, fluconazole, prednisone and voriconazole [52][53][54][55].…”

Clinical Significance of Measuring the Blood Concentration of Itraconazole Oral Solution in the Field of Hematology

“…We also reported that the administration of MCFG at 150 mg or less was effective in some patients. [20][21][22] In addition, approximately 25% of patients showed blood VRCZ levels exceeding a trough level at which liver dysfunction may occur, 4.5 mg/ml. We reviewed the clinical significance of measuring the blood level of VRCZ in the prevention of side effects, and reported that there was a gender difference in its blood level.…”