Effects of Hepatic CYP3A4 Activity on Disposition of Micafungin in Liver Transplant Recipients With Markedly Small-for-Size Grafts

Mochizuki, Nobuo; Matsumoto, K.; Ohno, Keiko; Shimamura, Tsuyoshi; Furukawa, Hiro; Todo, Satoru; Kishino, Satoshi

doi:10.1016/j.transproceed.2006.10.146

Cited by 16 publications

(12 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…14) Several reports have demonstrated that MCFG is a safe and effective antifungal agent, 9,[15][16][17] suggesting that dose adjustment is not required for elderly patients or patients with moderate liver dysfunction or severe kidney dysfunction. 9,12) However, information on the efficacy and safety of MCFG for the treatment of fungal infections in LDLT-recipients has been limited due to the small sample sizes of the studies reported previously [18][19][20] ; i.e., less than 9 LDLT-recipients in each study. In addition, there have been no reports concerning the efficacy and safety of MCFG in patients with severe liver dysfunction.…”

Section: Discussionmentioning

confidence: 99%

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

Iwamoto

Kagawa

Sakurai

et al. 2009

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

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 ...

show abstract

Section: Discussionmentioning

confidence: 99%

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

Iwamoto

Kagawa

Sakurai

et al. 2009

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

show abstract

“…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].…”

Section: Micafunginmentioning

confidence: 98%

Impact of special patient populations on the pharmacokinetics of echinocandins

Muilwijk¹,

Lempers²,

Burger³

et al. 2015

Expert Review of Anti-infective Therapy

View full text Add to dashboard Cite

Echinocandins belong to the class of antifungal agents. Currently, three echinocandin drugs are licensed for intravenous treatment of invasive fungal infections: anidulafungin, caspofungin and micafungin. While their antifungal activity overlaps, there are substantial differences in pharmacokinetics (PK). Numerous factors may account for variability in PK of echinocandins including age (pediatrics vs adults), body surface area and body composition (normal weight vs obesity), disease status (e.g., critically ill and burn patients) and organ dysfunction (kidney and liver impairment). Subsequent effects of altered exposure might impact efficacy and safety. Knowledge of PK behavior is crucial in optimal clinical utilization of echinocandin in a specific patient or patient population. This review provides up-to-date information on PK data of anidulafungin, caspofungin and micafungin in special patient populations. Patient populations addressed are neonates, children and adolescents, obese patients, patients with hepatic or renal impairment, critically ill patients (including burn patients) and patients with hematological diseases.

show abstract

“…In addition, we hypothesized that liver size may be an important factor affecting the contribution of the recipient and donor genotypes (Kishino et al, 2006;Lee et al, 2006;Mochizuki et al, 2006). Thus, we evaluated genotype and non-genotype factors using stepwise regression analysis and found that factors impacting patient tacrolimus blood concentrations in a descending order were: donor CYP3A5 genotype, recipient CYP3A5 genotype, time course, and age.…”

Section: Influence Of Age Time Course and Graft Liver Weight On Thementioning

confidence: 99%

Effect of CYP3A5 gene polymorphisms on tacrolimus concentration/dosage ratio in adult liver transplant patients

Wang¹,

Liu²,

Tong³

et al. 2015

Genet. Mol. Res.

View full text Add to dashboard Cite

ABSTRACT. We examined the influence of the cytochrome P450 3A5 (CYP3A5) genes in both donors and recipients on the concentrationdosage ratio (C/D) of tacrolimus in Chinese liver transplant patients. Fifty-one adult liver transplant patients who received tacrolimus were included in this study. The CYP3A5 polymorphism in donors and recipients was determined at the time of transplantation, and tacrolimusbased immunosuppressive therapy was started based on each patient's genetic constitution. The relationship between the C/D of tacrolimus for 3 months after surgery and the CYP3A5 genotype was analyzed. A stepwise regression model was used to analyze the relationship between C/D of tacrolimus and genotype, time course, age, and liver weight in liver transplant patients. Three months after liver transplantation, C/D was both affected by the CYP3A5 genotype of both the donors and (2015) the recipients. The C/D of tacrolimus in patients with the CYP3A5*1 allele or carrying CYP3A5*1 allele in the liver was lower than that in CYP3A5*3/*3 patients with the CYP3A5*3/*3 genotype in the liver (P < 0.01). The CYP3A5*1 genotype in donors as well as in patients both contributes to interindividual variation in the C/D of tacrolimus in adult liver transplantation.

show abstract

Effects of Hepatic CYP3A4 Activity on Disposition of Micafungin in Liver Transplant Recipients With Markedly Small-for-Size Grafts

Cited by 16 publications

References 3 publications

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

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

Impact of special patient populations on the pharmacokinetics of echinocandins

Effect of CYP3A5 gene polymorphisms on tacrolimus concentration/dosage ratio in adult liver transplant patients

Contact Info

Product

Resources

About