CYP3
Azole antifungal agent (triazole) [1]

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]。

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艾沙康唑 对1995年至2004年间收集的296株临床念珠菌血流分离株表现出强效体外活性。对所有菌株的MIC50为0.004 mg/L，MIC50/MIC90值范围从白色念珠菌的≤0.002/0.004 mg/L到光滑念珠菌的0.25/0.5 mg/L。
其活性（较低的MIC50）高于两性霉素B (0.5 mg/L)、伊曲康唑 (0.008 mg/L)、伏立康唑 (0.03 mg/L)、氟胞嘧啶 (0.125 mg/L) 和氟康唑 (8 mg/L)。
仅有两株光滑念珠菌分离株的MIC >0.5 mg/L（分别为2和4 mg/L），而包括氟康唑耐药株在内的所有其他菌株均高度敏感。[1]

动物模型（主要为小鼠）已用于剂量探索实验和疗效评估。在侵袭性肺曲霉病的小鼠模型中，曲线下面积与MIC比值 (AUC/MIC) 是药物疗效的主要预测指标。在免疫抑制小鼠的毛霉病模型研究中，艾沙康唑治疗可保护小鼠免受感染。其疗效也在播散性念珠菌病和隐球菌性脑膜炎模型中进行了评估。[3]

按照CLSI（原NCCLS）指南M27-A2进行肉汤微量稀释药敏试验。使用MOPS缓冲至pH 7.0的RPMI 1640培养基。最终接种浓度为0.5×10³至2.5×10³个细胞/mL。
将含有脱水抗真菌药物的微孔板在35°C下孵育24–48小时。通过肉眼观察确定MIC：对于两性霉素B，为无生长的最低浓度；对于唑类药物和氟胞嘧啶，为与无药对照相比生长减少≥50%的最低浓度。
使用质量控制菌株近平滑念珠菌ATCC 22019和克柔念珠菌ATCC 6258。[1]

Animal studies are described in general terms. Murine models of invasive fungal infections (e.g., invasive pulmonary aspergillosis, disseminated candidiasis, mucormycosis) are established in immunocompromised mice. The animals are infected with specific fungal strains (e.g., Aspergillus fumigatus). Isavuconazole is administered via specified routes (implied intravenously or orally, based on the active moiety from its prodrug), typically following a loading dose regimen to achieve steady-state levels rapidly. Efficacy endpoints include survival rates, fungal burden in target organs (e.g., kidneys, lungs), and histopathological analysis. [3]

Absorption, Distribution and Excretion
Following oral administration of 200 mg Isavuconazonium, the mean steady-state peak plasma concentration (Cmax) was 7499 ng/mL. After oral administration of 600 mg Isavuconazonium, the Cmax was 20028 ng/mL. It is estimated that the steady-state Cmax is reached approximately 2–3 hours after a single or multiple doses of Isavuconazonium. After oral and intravenous administration of 400 mg Isavuconazonium, the mean AUCs were 189462.8 hng/mL and 193906.8 hng/mL, respectively. Isavuconazonium can be taken with or without food, but the intake of high-fat foods concurrently reduces the Cmax of oral Isavuconazonium by 9% and increases the AUC by 9%. The absolute bioavailability of Isavuconazonium after a single oral dose is 98%. Following oral administration, 46.1% of the radiolabeled Isavuconazonium was detected in feces, and approximately 45.5% was recovered in urine. The amount of unmetabolized ixaconazole in urine is less than 1% of the total administered dose. The mean steady-state volume of distribution (Vss) after intravenous administration is approximately 450 L. The clearance (CL) of 200 mg ixaconazole administered orally or intravenously is 2.5 ± 1.6 L/h. Metabolites: Following the rapid esterase-mediated hydrolysis of the prodrug ixaconazole to ixaconazole, several minor metabolites were identified, in addition to the active moiety and its inactive cleavage products. However, no single metabolite was observed to have an AUC exceeding 10% of the total radiolabeled material. Based on in vivo and in vitro studies, the major enzymes involved in the metabolism of ixaconazole are CYP3A4, CYP3A5, and subsequently uridine diphosphate glucuronide transferase (UGT). Biological half-life: Based on population pharmacokinetic analysis in healthy subjects and patients, the mean plasma half-life of ixaconazole is 130 hours. The mean half-lives after oral and intravenous administration of 400 mg ixaconazole were 110 hours and 115 hours, respectively. The prodrug ixaconazole sulfate is rapidly hydrolyzed in plasma primarily by serum butylcholinesterase to the active antifungal drug ixaconazole and an inactive cleavage product. Neither the prodrug nor its cleavage product is detectable within 30 minutes after intravenous infusion or 2–3 hours after oral administration. The pharmacokinetics of ixaconazole are linear dose-proportional with low inter-patient variability (one study reported a steady-state concentration of 2.5 ± 1.0 μg/mL). Its oral bioavailability is excellent (approximately 98%) and is unaffected by food. It has a large volume of distribution (approximately 450 L), indicating its wide tissue distribution. The terminal half-life is approximately 130 hours. It is primarily eliminated via hepatic metabolism, with fecal excretion being the main route of elimination; renal excretion is less than 1% of the administered dose. Metabolism involves CYP3A4, CYP3A5, and uridine diphosphate glucuronide transferase (UGT). No dose adjustment is required for patients with mild to moderate hepatic impairment (Child-Pugh A or B) or renal impairment. Data for severe hepatic impairment (Child-Pugh C) are insufficient. Although this drug may not be cleared by hemodialysis, pharmacokinetic studies have not been conducted in dialysis patients. [3]

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information on the clinical use of ixaconazole during lactation. Because ixaconazole binds to plasma proteins at a rate exceeding 99%, its concentration in breast milk may be very low. However, there is currently no published experience regarding the use of ixaconazole during lactation; therefore, especially in breastfeeding newborns or premature infants, alternative medications may be preferred.
◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

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Protein Binding
Isavuconazonium has a high protein binding rate (greater than 99%), primarily binding to albumin.

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Isavuconazonium is generally well tolerated. In the SECURE study, ixacinazole significantly reduced drug-related adverse events (42.4%) compared to voriconazole (59.8%). Less common adverse events with ixacinazole include visual disturbances, elevated liver enzymes, and photosensitivity. Reported side effects include hypokalemia, peripheral edema, infusion-related reactions (e.g., acute respiratory distress, chills, dyspnea, hypotension), and gastrointestinal discomfort (nausea, vomiting, diarrhea). It has a unique dose- and concentration-dependent QT interval shortening effect (to 13 ms with 200 mg daily and 24.6 ms with 600 mg daily in healthy volunteers). It is contraindicated in patients with familial short QT syndrome. Ixacinazole is a moderate inhibitor of CYP3A4 and may lead to elevated plasma concentrations of drugs metabolized by this enzyme (e.g., sirolimus, tacrolimus, and cyclosporine) when taken concurrently, thus requiring therapeutic drug monitoring for these drugs. It should be avoided when used concurrently with potent CYP3A4 inducers (e.g., rifampin, carbamazepine). It is a pregnancy category C drug and will pass into breast milk. To date, no long-term side effects associated with voriconazole, such as skin malignancies and high fluoride poisoning/periodontitis, have been observed. [3]

[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
Isavuconazonium exhibits antifungal activity against most Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, and Mucorales fungi (such as Rhizopus oryzae and Mucor). In a cardiac electrophysiology study involving healthy subjects, ixaconazole caused a dose-dependent shortening of the QTc interval, but the additive effect of ixaconazole with other QTc prolonging drugs is unclear. Isavuconazonium is the active ingredient of the prodrug BAL8557, a water-soluble triazole prodrug suitable for oral and intravenous administration. It has broad-spectrum in vitro activity against a variety of major opportunistic fungi, including Candida, Cryptococcus, Aspergillus, Rhizopus, Mucor, and type II fungi. Currently, ixaconazole is in Phase III clinical development and is expected to be used to treat systemic Candida infections, including those caused by fluconazole-resistant strains. [1]

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。