CDK4/6; Abemaciclib metabolite

与abemaciclib类似，其主要代谢物LSN2839567和LSN3106726在体外生化和细胞基础试验中也具有相似的抑制CDK4和CDK6的作用，MCL患者的代谢物暴露剂量为200mg，每日两次，超过CDK4/cyclin D1和CDK6/cyclin D1的50%抑制浓度（IC50）。因此，暴露于abemaciclib及其活性代谢物与预期产生的生物活性是一致的。然而，基于暴露、疗效和安全性之间的关系，MCL中abemaciclib的最佳剂量需要进一步阐明。

Pharmacokinetic (PK) evaluations included assessing plasma concentrations of abemaciclib and its metabolites by liquid chromatography–mass spectrometry (LC-MS) method. The median abemaciclib tmax after a single dose was 5.7 hours (range, 3.9-8.0 hours) (Figure 1B). The mean (coefficient of variation) steady-state abemaciclib trough concentration was 364 ng/mL (85%), indicating a high degree of interindividual variability in exposure. After single and multiple doses of abemaciclib, the mean accumulation ratio based on Cmax was 2.14 for abemaciclib and 3.91 to 5.17 for its metabolites, LSN2839567, LSN3106726, and LSN3106729 (Online Supplementary Table S3).[2]

[1]. WO2017180389A1.

[2]. Haematologica. 2021 Mar 1;106(3):859-862.

Mantle cell lymphoma (MCL) accounts for ~6% of all non-Hodgkin lymphomas (NHL) with an aggressive clinical course in patients, especially after early relapse. Lack of cure for relapsed/refractory (R/R) MCL with conventional therapy has resulted in a search for targeted therapies. CDK4 and CDK6 inhibitors have emerged as therapeutic options for R/R MCL because MCL cell lines and patient-derived samples that express high levels of cyclin D1 are highly sensitive to CDK4 and CDK6 inhibitors. Oral abemaciclib is a potent and selective CDK4 and CDK6 inhibitor that reduced tumor growth in human xenograft models with MCL. In a phase I study of patients with MCL, palbociclib, another CDK4 and CDK6 inhibitor, was shown to overcome resistance to ibrutinib, a first-in-class bruton tyrosine kinase (BTK) inhibitor. Here, we evaluated the efficacy, safety, and pharmacokinetic profile of abemaciclib in patients with R/R MCL in a phase II trial.[2]

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In conclusion, this study demonstrated that singleagent abemaciclib dosed on a continuous schedule has clinical activity in patients with R/R MCL who received multiple prior systemic therapies. The safety profile of abemaciclib in this patient group is generally consistent with other abemaciclib studies on advanced breast cancer except for higher thrombocytopenia. Additional clinical trials of abemaciclib in combination with current preferred therapies such as a BTK inhibitors are needed to determine the synergistic effects and positioning of CDK4 and CDK6 inhibitors in MCL.[2]

C27H32F2N8O

522.592791557312

522.27

C, 62.05; H, 6.17; F, 7.27; N, 21.44; O, 3.06

2138499-06-4

Abemaciclib metabolite M20-d8

139600311

Light yellow to yellow solid powder

2.6

95.2

2

10

8

38

744

0

KUJBDJBMXOTNIT-UHFFFAOYSA-N

InChI=1S/C27H32F2N8O/c1-4-35-7-9-36(10-8-35)15-18-5-6-23(30-13-18)32-27-31-14-21(29)25(34-27)19-11-20(28)26-22(12-19)37(17(2)3)24(16-38)33-26/h5-6,11-14,17,38H,4,7-10,15-16H2,1-3H3,(H,30,31,32,34)

[6-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-4-fluoro-1-propan-2-ylbenzimidazol-2-yl]methanol

CDK4/6 IN 4; CDK4/6-IN-4; CDK4/6-IN 4; Abemaciclib metabolite M20; 2138499-06-4; CDK4/6-IN-4; LSN3106726; [6-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-4-fluoro-1-propan-2-ylbenzimidazol-2-yl]methanol; SCHEMBL23387651; CDK4/6 IN-4

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: ~5 mg/mL (~9.6 mM)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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。