Maribavir   中文名称: 马立巴韦

HCMV

Maribavir 的平均 IC50 为 35 nM，是野生型和已研究的所有主要更昔洛韦 (GCV) 抗性 UL97 突变体的自磷酸化的强抑制剂。 M460I 突变的 IC50 为 4.8 nM，会导致对马利巴韦过敏。 L397R 是一种对马里巴韦耐药的 UL97 突变体，其更昔洛韦激酶和蛋白激酶的功能降低（约为野生型水平的 10%）。 Maribavir 是一种 ATP 竞争性抑制剂，酶动力学研究表明 Ki 为 10 nM [1]。使用多循环 DNA 杂交测定，maribavir (1263W94) 以剂量依赖性方式抑制病毒复制，IC50 为 0.12±0.01 μM。 Maribavir 显着抑制 pUL97 蛋白激酶，在 3 nM 时抑制 50% [2]。

使用浓度不断增加的 ATP（2 μM 至 20 μM），对纯化的野生型和突变型 UL97 蛋白进行酶动力学分析。为了计算每个 UL97 物种的 ATP 的 Km，将掺入的放射性标记磷酸盐的量相对于 ATP 的浓度绘制在 Lineweaver Burke 图中。蛋白激酶测定用于测量 Maribavir 对野生型或突变型 UL97 放射性标记磷酸盐掺入率的影响。如前所述，测定可以在固定浓度 0.55 μM Maribavir 下进行，也可以在增加浓度的 Maribavir 下进行。 0.01 μM 至 5.0 μM Maribavir，以确定 Maribavir 对每种 UL97 的 IC50。随着 Maribavir 浓度的增加，创建 1/v 与 1/ATP 的图，以确定 Maribavir 介导的抑制类型。如果线族在 y 轴上收敛于 1/Vmax，则存在明显的竞争性抑制证据。 Ki 是利用添加 Maribavir 所带来的斜率变化来计算的[1]。

MRC-5 细胞以大约 5×104 个细胞/孔的密度接种到 24 孔板中后，在 MEM 8-1-1 中培养三天直至汇合（~1.1×105 个细胞/孔）。在MEM 2-1-1中，用AD169以1至3的感染复数(MOI)感染细胞，并让感染在37℃吸附90分钟。添加一毫升 MEM 2-1-1 代替未吸附的病毒。 Maribavir、BDCRB 或 GCV 以每个实验指定的浓度添加到培养基中，以检查这些化合物对病毒 DNA 合成或成熟的影响[2]。

Absorption, Distribution and Excretion
Population pharmacokinetic modeling in patients receiving maribavir 400mg twice daily showed an AUC0-tau and Cmax of 128 µg.h/mL and 17.2 µg/mL, respectively. It has a median Tmax of one to three hours.
Maribavir is eliminated primarily via hepatic metabolism. Following the oral administration of radiolabeled maribavir, 61% of the dose was excreted in the urine (<2% as unchanged drug) and 14% was excreted in the feces (5.7% as unchanged drug).
The mean apparent steady-state volume of distribution for maribavir was 27.3 L.
In post-transplant patients, the mean oral clearance of maribavir was 2.85 L/h.

---

Metabolism / Metabolites
Maribavir is extensively metabolized following oral administration, primarily by CYP3A4 and, to a lesser extent, by CYP1A2. Its major circulating metabolite is VP 44469, an inactive N-dealkylated metabolite.

---

Biological Half-Life
In post-transplant patients, the mean half-life of elimination was 4.32 hours.

Hepatotoxicity
In large preregistration clinical trials, ALT elevations occurred in 3.5% of maribavir vs less than 1% of standard therapy in recipients with refractory CMV infection after hematopoietic cell transplantation. The ALT elevations were transient, mild and asymptomatic. In prelicensure studies, there were no instances of clinically apparent liver injury with jaundice. Since the approval of maribavir and its general availability, there have been no reported cases of clinically apparent liver injury with jaundice associated with its use; however, the total clinical experience with maribavir therapy is limited.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

---

Protein Binding
Across all concentration ranges tested, maribavir was extensively (~98%) protein-bound in plasma, likely primarily to serum albumin and alpha-1-acid glycoprotein.

[1]. The effects of Maribavir on the autophosphorylation of ganciclovir resistant mutants of the cytomegalovirus UL97 protein. Herpesviridae. 2010 Dec 7;1(1):4.

[2]. Potent and selective inhibition of human cytomegalovirus replication by 1263W94, a benzimidazole L-riboside with a unique mode of action. Antimicrob Agents Chemother. 2002 Aug;46(8):2365-72.

Maribavir is an inhibitor of the cytomegalovirus (CMV; HHV5) pUL97 kinase which is used to treat CMV infections in patients post-transplantation. Most standard CMV therapies, such as [ganciclovir] or [foscarnet], target CMV DNA polymerase - while generally effective, these medications tend to promote the development of CMV resistance to DNA polymerase-based therapies, and their use is often limited by toxicities like myelosuppression and renal injury. Maribavir is novel in that it instead targets the CMV pUL97 kinase, thereby providing an effective alternative treatment option in cases of resistant infections. Maribavir was approved by the FDA in November 2021, under the name Livtencity (Takeda), for the treatment of resistant CMV infections in post-transplant patients. The drug was also approved by Health Canada in September 2022 and by European Commission in November 2022.
Maribavir is a Cytomegalovirus pUL97 Kinase Inhibitor. The mechanism of action of maribavir is as a Cytomegalovirus pUL97 Kinase Inhibitor, and Cytochrome P450 3A4 Inhibitor, and P-Glycoprotein Inhibitor, and Breast Cancer Resistance Protein Inhibitor.
Maribavir is an orally available, antiviral agent which inhibits the pUL97 kinase of cytomegalovirus (CMV) and is used to treat refractory forms of post-transplant CMV infection. Maribavir has been associated with low rates of mild-to-moderate serum aminotransferase elevations during therapy but has not been linked to cases of clinically apparent acute liver injury.
Maribavir is an orally available benzimidazole riboside compound with activity against cytomegalovirus (CMV). Maribavir is a selective ATP competitor of viral UL97 kinase, which is involved in viral nuclear maturation events, such as viral DNA assembly and movement of viral capsids from the nucleus of infected cells. Maribavir has activity against strains of CMV that are resistant to standard anti-CMV agents.

---

Drug Indication
Maribavir is indicated for the treatment of post-transplant cytomegalovirus (CMV) infection (following hematopoietic stem cell transplant or solid organ transplant) which is refractory to standard treatment with [ganciclovir], [valganciclovir], [cidofovir], or [foscarnet]. In the US, patients receiving the treatment should weigh more than 35 kg and be at least 12 years old. In Canada and Europe, maribavir is only approved in adults.
LIVTENCITY is indicated for the treatment of cytomegalovirus (CMV) infection and/or disease that are refractory (with or without resistance) to one or more prior therapies, including ganciclovir, valganciclovir, cidofovir or foscarnet in adult patients who have undergone a haematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT). Consideration should be given to official guidance on the appropriate use of antiviral agents.
Treatment of cytomegalovirus (CMV) infection
Cytomegaloviral disease

---

Mechanism of Action
Human cytomegalovirus (CMV) is a herpesvirus commonly causing infection in patients following stem cell or organ transplants. As with other herpesviruses, CMV tends to persist in the host and become reactivated under immunosuppressive conditions - patients requiring multiple immunosuppressive medications to combat transplant rejection are thus at a much higher risk of developing serious CMV infections. Maribavir belongs to a class of anti-cytomegalovirus antivirals called benzimidazole ribosides. It competitively inhibits the human CMV pUL97 viral protein kinase, which results in viable but severely defective viruses upon replication, although the reasons for this remain poorly defined. In addition, maribavir also inhibits viral release from the nucleus to the cytoplasm by inhibiting pUL97-dependent phosphorylation of the nuclear lamina component lamin A/C, although the extent to which this activity contributes to its antiviral efficacy is unclear.

---

Pharmacodynamics
Maribavir exerts its antiviral efficacy via an alternative target as compared to traditional CMV antivirals and is thus useful in the treatment of CMV infections that have proven resistant to standard therapy. Maribavir should not be used concomitantly with ganciclovir or valganciclovir, as these molecules both require activation via CMV pUL97 in order to exert their antiviral effect. Taking them alongside maribavir - an inhibitor of this same kinase - will therefore significantly reduce their antiviral activity.

C15H19CL2N3O4

376.23506

375.075

C, 47.89; H, 5.09; Cl, 18.84; N, 11.17; O, 17.01

176161-24-3

471161

Solid powder

1.7±0.1 g/cm3

611.0±65.0 °C at 760 mmHg

323.3±34.3 °C

0.0±1.8 mmHg at 25°C

1.703

2.71

99.77

4

6

4

24

447

4

ClC1=C(Cl)C=C2C(N=C(NC(C)C)N2[C@@H]3[C@@H](O)[C@@H](O)[C@H](CO)O3)=C1

KJFBVJALEQWJBS-XUXIUFHCSA-N

InChI=1S/C15H19Cl2N3O4/c1-6(2)18-15-19-9-3-7(16)8(17)4-10(9)20(15)14-13(23)12(22)11(5-21)24-14/h3-4,6,11-14,21-23H,5H2,1-2H3,(H,18,19)/t11-,12-,13-,14-/m0/s1

5,6-Dichloro-2-(isopropylamino)-1-beta-L-ribofuranosyl-1H-benzimidazole

1263-W94; GW-1263; SHP-620; 1263 W94; 1263W-94; BW1263W 94; GW1263; SHP620; BW-1263W94; VP41263; Livtencity; BW 1263W94; VP-41263; GW-257406X; GW257406-X; GW 257406X; GW 257406 X; GW257406X

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 : ~200 mg/mL (~531.58 mM)

配方 1 中的溶解度: ≥ 2.87 mg/mL (7.63 mM) (饱和度未知) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
*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。

---

配方 2 中的溶解度: ≥ 2.87 mg/mL (7.63 mM) (饱和度未知) in 5% DMSO + 95% (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。
*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。

---

View More

配方 3 中的溶解度: ≥ 2.5 mg/mL (6.64 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。
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。

---

配方 4 中的溶解度: ≥ 2.5 mg/mL (6.64 mM) 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100μL 25.0mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，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。

---

配方 5 中的溶解度: ≥ 2.5 mg/mL (6.64 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。

---

配方 6 中的溶解度: 5% DMSO+40% PEG300+5% Tween-80+50% Saline: ≥ 2.87 mg/mL (7.63 mM)

---

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。