Odevixibat   中文名称: 奥维昔巴特

Odevixibat (A4250)（饲料中 0.01%（w/w）；4 周）可改善硬化性胆管炎，显着降低血清 BA、碱性磷酸酶和丙氨酸转氨酶水平，以及促炎和促纤维化基因的表达Mdr2-/-小鼠的肝脏和胆管增殖[1]。此外，在刺激 Ntcp 和 Cyp7a1 的同时，Odevixibat (A4250) 显着降低胆汁通量和胆汁 BA 输出，这与 bsep 转录减少相一致 [1]。

Animal/Disease Models: Eightweeks old Mdr2-/- (Abcb4-/-) mice (cholestatic liver injury and sclerosing cholangitis model) [1]
Doses: 0.01% (w/w) in feed Administration time: 4-week
Experimental Results: Cholestasis diminished in mouse liver and bile duct injury model.

Absorption, Distribution and Excretion
A 7.2 mg single oral dose of odevixibat in adults reaches a Cmax of 0.47 ng/mL, with an AUC0-24h of 2.19 h\*ng/mL. The majority of adult and pediatric patients, given a therapeutic dose, do not have detectable plasma concentrations of odevixibat.
Odevixibat is 82.9% recovered in the feces and <0.002% recovered in the urine. The dose recovered in the feces is 97% unchanged parent compound.
The majority of adult and pediatric patients, given a therapeutic dose, do not have detectable plasma concentrations of odevixibat. Therefore, a volume of distribution has not been calculated.
The majority of adult and pediatric patients, given a therapeutic dose, do not have detectable plasma concentrations of odevixibat. Therefore, the clearance has not been calculated.

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Metabolism / Metabolites
Odevixibat is largely unmetabolized, however a small amount is metabolized _in vitro_ by mono-hydroxylation. The exact structure of the metabolite has not been characterized as a primary endpoint of the clinical trial was to characterize the structure of metabolites accounting for >10% of the dose in plasma, urine, or feces. No metabolites have been identified at such a high concentration.

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Biological Half-Life
A 7.2 mg oral dose of odevixibat has a mean half life of 2.36 hours in adults.

Hepatotoxicity
In trials of odevixibat in children with cholestatic liver diseases, serum ALT elevations of greater than 3 times ULN arose in 8% to 11% of treated participants and were particularly common with long term therapy. However, children with PFIC typically have serum ALT and AST elevations, and it was difficult to establish whether mild-to-moderate serum enzyme elevations were due to odevixibat therapy or to the spontaneous fluctuations that occur with the underlying disease. Clinically apparent liver injury with jaundice or hepatic decompensation has not been reported in children treated with odevixibat, although the total clinical experience with its use is limited.
Likelihood score: E* (suspected but unproven cause of clinically apparent liver injury).

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Protein Binding
Due to the low systemic abosrption of odevixibat, plasma protein binding studies could not be performed _in vivo_. Odevixibat is >99% protein bound _in vitro_.

[1]. Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis.J Hepatol. 2016 Mar;64(3):674-81.

Odevixibat, or A4250, is an ileal sodium/bile acid cotransporter inhibitor indicated for the treatment of pruritus in patients older than 3 months, with progressive familial intrahepatic cholestasis (PFIC). Odevixibat is the first approved non-surgical treatment option for PFIC. Previous therapies for PFIC included a bile acid sequestrant such as [ursodeoxycholic acid]. Odevixibat was granted FDA and Health Canada approval on 20 July 2021 and 13 November 2023 respectively.
Odevixibat is an Ileal Bile Acid Transporter Inhibitor. The mechanism of action of odevixibat is as an Ileal Bile Acid Transporter Inhibitor.
Odevixibat is an orally available inhibitor of the ilieal bile salt transporter which is used to treat severe pruritus in patients with cholestatic liver disease such as progressive familial intrahepatic cholestasis. Odevixibat is associated with transient serum enzyme elevations particularly with long term therapy but has not been linked to instances of clinically apparent liver injury with jaundice, although experience with its use has been limited.

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Drug Indication
Odevixibat is indicated for the treatment of pruritus in patients older than 3 months and 6 months with progressive familial intrahepatic cholestasis (PFIC) by the FDA and Health Canada respectively. It is also indicated for the treatment of cholestatic pruritus in patients 12 months of age and older with Alagille Syndrome. Odevixibat may not be effective in patients with PFIC type 2 with ABCB11 variants since these patients lack a functional bile salt export pump.
Bylvay is indicated for the treatment of progressive familial intrahepatic cholestasis (PFIC) in patients aged 6 months or older (see sections 4. 4 and 5. 1).
Treatment of Alagille syndrome
Treatment of Progressive Familial Intrahepatic Cholestasis
Treatment of biliary atresia

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Mechanism of Action
Progressive familiar intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders leading to cholestasis, fibrosis, and eventually a need for liver transplantation. Patients with PFIC require liver transplants or develop hepatocellular carcinomas in their first few years of life. Many of these patients experience severe pruritus. The exact mechanism of pruritus is PFIC is not known, but lower concentrations of bile acids have been shown to reduce pruritus. Patients with certain forms of PFIC type 2, associated with a non-functional or absent bile salt export pump, are not expected to benefit from odevixibat treatment. The ileal sodium/bile acid cotransporter is a transport glycoprotein responsible for reabsorption of 95% of bile acids in the distal ileum. Odevixibat is a reversible inhibitor of the ileal sodium/bile acid contransporter. Patients taking odevixibat for a week experienced a 56% reduction in bile acid area under the curve with a 3 mg once daily dose. A 1.5 mg daily dose lead to a 43% reduction in bile acid area under the curve. The decreased reabsorption of bile acids, leads to reduced stimulation of FXR, which reduces expression of FGF19, reducing binding of FGF19 to FGF4R, decreasing inhibition of bile acid synthesis. Further synthesis of bile acids that will not be reabsorbed in the intestine contributes to lowering low density lipoprotein levels.

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Pharmacodynamics
Odevixibat, or A4250, is an ileal sodium/bile acid cotransporter inhibitor indicated for the treatment of pruritus in patients older than 3 months, with progressive familiar intrahepatic cholestasis (PFIC). It has a moderate duration of action as it is given once daily. Odevixibat has a wide therapeutic index as patients were given single doses up to 10 mg while the maximum therapeutic dose is 6 mg daily. Patients should be counselled regarding the risks of elevated liver function tests, diarrhea, and fat soluble vitamin defiencies.

C37H48N4O8S2

740.93

740.291

501692-44-0

501692-44-0;2409081-01-0 (hydrate);Odevixibat HCl;

10153627

White to off-white solid powder

1.3±0.1 g/cm3

1.643

7.03

208

5

11

17

51

1230

2

CCCCC1(CN(C2=CC(=C(C=C2S(=O)(=O)N1)OCC(=O)N[C@H](C3=CC=C(C=C3)O)C(=O)N[C@@H](CC)C(=O)O)SC)C4=CC=CC=C4)CCCC

XULSCZPZVQIMFM-IPZQJPLYSA-N

InChI=1S/C37H48N4O8S2/c1-5-8-19-37(20-9-6-2)24-41(26-13-11-10-12-14-26)29-21-31(50-4)30(22-32(29)51(47,48)40-37)49-23-33(43)39-34(25-15-17-27(42)18-16-25)35(44)38-28(7-3)36(45)46/h10-18,21-22,28,34,40,42H,5-9,19-20,23-24H2,1-4H3,(H,38,44)(H,39,43)(H,45,46)/t28-,34+/m0/s1

(S)-2-((R)-2-(2-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2,5]thiadiazepin-8-yl)oxy)acetamido)-2-(4-hydroxyphenyl)acetamido)butanoic acid

AZD8294 A4250 AR-H064974AZD-8294 A-4250 AR-H-064974Bylvay

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮。

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

DMSO : ~166.67 mg/mL (~224.95 mM)

配方 1 中的溶解度: ≥ 4.17 mg/mL (5.63 mM) (饱和度未知) 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。
例如，若需制备1 mL的工作液，可将100 μL 41.7 mg/mL澄清的DMSO储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入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: ≥ 4.17 mg/mL (5.63 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 41.7mg/mL澄清DMSO储备液加入900μL玉米油中，混合均匀。

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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。