Caspofungin versus micafungin in the incidence of hepatotoxicity in patients with normal to moderate liver failure.

BACKGROUND: One of the major adverse events of caspofungin and micafungin is hepatotoxicity, however, there are few reports compared the incidence of hepatotoxicity between caspofungin and micafungin. Herein, the primary objective of this study was to compare the incidence of hepatotoxicity between caspofungin and micafungin treatments for patients with fungal or suspected fungal infection. METHODS: In total, 201 patients [caspofungin group: 66 patients; micafungin group: 135 patients] treated with echinocandins from April 2014 to November 2015 at Aichi Medical University Hospital. Investigation item were as follows; sex, age, weight, height, duration of treatment, total dose, disease type, clinical isolates, liver enzyme levels, concomitant medications. Liver function was assessed in accordance with Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. We divided into two groups depend on their liver enzyme levels before treated with echinocandins; normal group (liver enzyme levels ≤ CTCAE Grade 1), abnormal group (liver enzyme levels ≥ CTCAE Grade 2). RESULTS: The overall incidence of serious hepatotoxicity (Grade 3 or higher) was 6.1% (4/66) in the caspofungin group and 7.4% (10/135) in the micafungin group. The proportion of patients used caspofungin and micafungin showed serious hepatotoxicity were 0% (0/47) and 6.5% (7/108) in normal group (p = 0.17), and 21.1% (4/19) and 10.7% (3/28) in abnormal group (p = 0.42). CONCLUSION: There was no notable difference in serious hepatotoxicity between the caspofungin group and the micafungin group, even though in patients with abnormal liver enzyme levels (CTCAE grade 2 or higher).

[Evaluation of voriconazole oral dosage in Japan].

Voriconazole (VRCZ), a broad-spectrum triazole, is served in two dosage forms-injection and oral. VRCZ is difference dosage of oral and intravenous administration writing a medical package insert in Japan. 6 mg/kg intravenous injection (IV) twice daily for first day as initial loading dose, followed by 3-4 mg/kg IV twice daily between meals is recommended. 300 mg orally twice daily for first day as initial loading dose, followed by 150-200 mg orally twice daily between meals is recommended. Patients weighing over 40 kg, 200 mg orally twice daily between meals is recommended. Patients weighing under 40 kg, 100 mg orally twice daily between meals is recommended, increase to 150 mg twice daily if inadequate response. This study evaluated VRCZ trough concentration and oral dosage in the 23 cases which administered VRCZ to analysis for TDM in Aichi University Hospital. Spearman rank correlation coefficient was calculated to examine relationships among variables. The level of statistical significance was set at p=0.05. All data were analyzed and processed on JMP 8 (SAS Institute Japan). There was a significant positive correlation between VRCZ trough concentration and dose/weight (r=0.47 p<0.05). In this result, VRCZ oral dosage is appropriate to administer dose/weight (mg/kg) twice a day as same as IV.

[Clinical investigation of arbekacin sulfate based on Cmax/MIC].

We examined the peck concentration (Cmax)/minimal inhibitory concentration (MIC) and the clinical efficacy in methicillin-resistant Staphylococcus aureus (MRSA) pneumonia and Gram-positive cocci bacteremia. We evaluated arbekacin (ABK) on 22 cases of pneumonia and 10 cases of bacteremia in Aichi Medical University Hospital between August 2008 and July 2011, retrospectively. In pneumonia cases, Cmax/MIC was 16.4 +/- 2.8 in the effective group, and was 17.6 +/- 4.5 in the not effective group, the significant differences were not accepted (p = 0.8). The dosage of ABK was 4.7 +/- 1.4 mg/kg/dose in the effective group and was 4.3 +/- 0.7 mg/kg/dose in the not effective group. In bacteremia cases, Cmax/MIC was 24.2 +/- 13.9 in the effective group and 12.9 +/- 3.9 in the not effective group about clinical efficacy, and the high tendency was accepted by the effective group (p < 0.05). The dosage of ABK was 3.4 +/- 1.1 mg/kg/dose in the effective group, and 3.0 +/- 0.6 mg/kg/dose in the not effective group. In this examination, the significant difference was not observed in clinical efficacy and Cmax/MIC in the pneumonia cases. Although it was reported that clinical efficacy of ABK was given Cmax/MIC at eight or more, in this examination, all cases was eight or more at Cmax/MIC, and the clinical effect was 40.9%. On Cmax/MIC of ABK, clinical effective group was higher than not effective group in bacteremia cases, it was suggested that the administration design should make that Cmax/MIC at least about 14 or more would be necessary.

[Clinical implication of therapeutic drug monitoring on voriconazole from the aspect of the analysis for CYP2C19 gene].

Three microsome enzymes are involved in voriconazole (VRCZ) metabolism, CYP2C19, CYP3A4 and CYP2C9, and subjects classified as poor metabolizers (PM), which would include about 20% of Japanese population, had higher serum VRCZ concentrations than other subjects. Also, because VRCZ appears hepatotoxicity and visual disturbance in side effect, VRCZ must be done therapeutic drug monitoring (TDM). This study evaluated the three cases which administered VRCZ to analysis for CYP2C19 gene. This study evaluated VRCZ trough concentration and side effect in the fifteen cases which administered VRCZ to analysis for TDM in Aichi University Hospital. Also, the administering design of VRCZ followed drug information in the three cases. Correlation of VRCZ trough concentration and dosage was weak in fifteen cases. In case 1, although patient is not PM, trough concentration of VRCZ showed high concentration (8.43 microg/mL) after 4 days of starting administration and appeared side effects of illusion and optical illusion. In case 2, although patient is PM, trough concentration of VRCZ showed 5.53 microg/mL and 8.61 microg/mL after 4 days and 7 days of starting administration, respectively, also liver function (AST, ALT and others) rised slightly. In case 3, although patient is not PM, trough concentration of VRCZ after the 5 days and 12 days of starting administration showed 3.2 microg/mL and 3.25 microg/mL, respectively, also maintained therapeutic trough lebel. In this result, it was thought that pharmacokinetics of VRCZ was unstable comparatively and concentration of VRCZ varied generally among individuals regardless of the CYP2C19 genotype. Therefore, it was important to an individual patient to improve a clinical effect, and to decrease the adverse event from the initial administering design, and is necessary to do the administering design afterwards while doing TDM at many times.

Role of plasma proteins in pharmacokinetics of micafungin, an antifungal antibiotic, in analbuminemic rats.

There were no significant differences in the pharmacokinetics of micafungin and expression of hepatic multidrug resistance-associated protein 2 (ABCC2/Mrp2) between analbuminemic and Sprague-Dawley rats. Micafungin bound strongly to high-density lipoprotein (HDL) and moderately to gamma globulin. These results suggest that HDL and gamma globulin contribute to the pharmacokinetics of micafungin.