CYP3

艾沙康唑 (BAL-4815) 的活性 MIC50 为 0.004 mg/L，对所有念珠菌属均表现出良好的活性。对于白色念珠菌，MIC50s/MIC90s 范围为 0.002/0.004 mg/L 至 0.25/0.5 mg/L[1]。在体外，艾沙康唑可有效抑制紫紫紫霉、尖端Scedosporium apiospermum 和大多数常见曲霉属物种[2]。艾沙康唑对酵母、霉菌和二态性真菌具有很强的作用。艾沙康唑对根霉分离株的最低抑菌浓度 (MIC) 范围为 0.12 µg/mL 至 32 µg/mL [3]。在针对 GFP 转化体 F/11628、NIH 4215 和 F/16216 的药代动力学和药效学研究中，艾沙康唑的模式最低抑制浓度 (MIC) 分别为 1、8、1 和 4 mg/L[4]。

Absorption, Distribution and Excretion
Following oral administration of 200 mg isavuconazole, the mean peak plasma concentration (Cmax) at steady state was 7499 ng/mL. Cmax following oral administration of 600 mg isavuconazole was 20028 ng/mL. It is proposed that the Cmax at steady state is reached approximately 2–3 hours after single and multiple dosing of isavuconazole. Administration of 400 mg of oral and intravenous isavuconazole resulted in mean AUC of 189462.8 h*ng/mL and 193906.8 h*ng/mL, respectively. While isavuconazole can be administered with or without food, concurrent consumption of a high-fat meal reduced oral isavuconazole Cmax by 9% and increased AUC by 9%. The absolute bioavailability of isavuconazole following oral administration of a single dose of isavuconazole is 98%.
Following oral administration, 46.1% of total radiolabelled isavuconzaole was detected in the feces, and about 45.5% was recovered in urine. Unchanged isavuconazole in the urine was less than 1% of the total dose administered.
The mean steady state volume of distribution (Vss) was approximately 450 L following intravenous administration.
The clearance (CL) rate was 2.5 ± 1.6 L/h in patients receiving 200 mg isavuconazole orally or intravenously.

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Metabolism / Metabolites
Following rapid conversion of the prodrug isavuconazonium to isavuconazole via esterase-mediated hydrolysis, a number of minor metabolites were identified in addition to the active moiety itself and the inactive cleavage product of isavuconazonium. However, no individual metabolite was observed with an AUC greater than 10% of total radio-labeled material. The main enzymes involved in the metabolism of isavuconazole are CYP3A4, CYP3A5, and subsequently uridine diphosphate- glucuronosyltransferases (UGT) according to the findings of _in vivo_ and _in vitro_ studies.

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Biological Half-Life
Based on a population pharmacokinetics analysis of healthy subjects and patients, the mean plasma half-life of isavuconazole was 130 hours. The mean half life following oral and intravenous administration of 400 mg isavuconazole was 110 and 115 hours, respectively.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of isavuconazole during breastfeeding. Because isavuconazole is more than 99% bound to plasma proteins, the amount in milk is likely to be low. However, there is no published experience with isavuconazole during breastfeeding, so an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Isavuconazole is highly protein bound (greater than 99%), predominantly to albumin.

[1]. In vitro activities of isavuconazole and other antifungal agents against Candida bloodstream isolates. Antimicrob Agents Chemother. 2007 May;51(5):1818-21.

[2]. In Vitro Activity of Isavuconazole against Rasamsonia Species. Antimicrob Agents Chemother. 2016 Oct 21;60(11):6890-6891.

[3]. Isavuconazole in the treatment of invasive aspergillosis and mucormycosis infections. Infect Drug Resist. 2016 Jun 2;9:79-86.

[4]. Pharmacodynamics of Isavuconazole in a Dynamic In Vitro Model of Invasive Pulmonary Aspergillosis. Antimicrob Agents Chemother. 2015 Oct 26;60(1):278-87.

[5]. Evaluation of the pharmacokinetics and clinical utility of isavuconazole for treatment of invasive fungal infections. Expert Opin Drug Metab Toxicol. 2012 Jun;8(6):759-65.

Pharmacodynamics
Isavucoanzole exhibits antifungal activity against most strains of _Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger_, and Mucorales such as _Rhizopus oryzae_ and Mucormycetes species _in vivo_ and _in vitro_. In a cardiac electrophysiology study involving healthy subjects, isavuconazole induced dose-related shortening of the QTc interval but the additive effect of isavuconazole with other QTc-prolonging drug is unknown.

C22H17F2N5OS

437.4651

437.112

C, 60.40; H, 3.92; F, 8.69; N, 16.01; O, 3.66; S, 7.33

241479-67-4

Isavuconazole-d4;1346598-58-0

6918485

Solid powder

1.38

678ºC at 760 mmHg

363.8ºC

4.242

115.86

1

8

6

31

657

2

S1C([H])=C(C2C([H])=C([H])C(C#N)=C([H])C=2[H])N=C1[C@]([H])(C([H])([H])[H])[C@@](C1C([H])=C(C([H])=C([H])C=1F)F)(C([H])([H])N1C([H])=NC([H])=N1)O[H]

DDFOUSQFMYRUQK-RCDICMHDSA-N

InChI=1S/C22H17F2N5OS/c1-14(21-28-20(10-31-21)16-4-2-15(9-25)3-5-16)22(30,11-29-13-26-12-27-29)18-8-17(23)6-7-19(18)24/h2-8,10,12-14,30H,11H2,1H3/t14-,22+/m0/s1

4-(2-((2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)thiazol-4-yl)benzonitrile

BAL4815; RO0094815; BAL-4815; RO 0094815; BAL 4815; RO-0094815; Isavuconazole; trade name Cresemba.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 50~87 mg/mL ( 114.29~198.87 mM )
Ethanol : ~87 mg/mL

配方 1 中的溶解度: 2.5 mg/mL (5.71 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (5.71 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (5.71 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 10% DMSO+40% PEG300+5% Tween-80+45% Saline

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。