与重组人 TPO (rhTPO) 一样，avatrombopag (E5501；AKR-501) 特异性结合 TPO 受体，并在整个巨核细胞发育和成熟过程中诱导巨核细胞生成 [1]。 avatrombopag (0-100 nM) 以浓度依赖性方式促进表达 TPO 受体的 Ba/F3 细胞的生长。与 rhTPO 类似，avatrombopag (0-3 μM) 会导致细胞中 STAT3 和 STAT5 的酪氨酸磷酸化以及 ERK 的苏氨酸磷酸化 [1]。在人 CD34+ 细胞中，avatrombopag 以浓度依赖性方式刺激巨核细胞集落的发育。 Avatrombopag 的 EC50 为 25 nM，最大活性与 rhTPO 相当[1]。

移植人 FL CD34+ 细胞的 NOD/SCID 小鼠在给予 avatrombopag（0.3-3 mg/kg；口服；每天一次，持续 14 天）时，具有更高的人血小板计数[1]。

细胞增殖测定 [1]
细胞类型： Ba/F3 细胞
测试浓度： 0.003 μM、0.03 μM、0.3 μM、3 μM
孵育时间：
实验结果：以浓度依赖性方式表达 TPO 受体的 Ba/F3 细胞增殖增加。

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蛋白质印迹分析 [1]
细胞类型： Ba/F3 细胞
测试浓度： 0.003 μM、0.03 μM、0.3 μM , 3 μM
孵育时间： 15 分钟
实验结果： 诱导细胞内 STAT3 和 STAT5 酪氨酸磷酸化以及 ERK 酸磷酸化苏氨酸。

Animal/Disease Models: NOD/SCID (severe combined immunodeficient) mouse (transplanted with human FL CD34+ cells) [1]
Doses: 0.3, 1, and 3 mg/kg
Route of Administration: Po; one time/day for 14 days
Experimental Results: Human platelet counts were dose-dependent The increase was approximately 2.7-fold at 1 mg/kg/d and approximately 3.0-fold at 3 mg/kg/d on day 14 after initiation of administration.

Absorption, Distribution and Excretion
Following single dosing under fasted and fed conditions, mean peak concentrations occurred at 5-8 hours and declined with a half-life of 16-18 hours in Japanese and white subjects. Administration with food did not have an effect on the rate or extent of avatrombopag absorption, however, significantly reduced pharmacokinetic variability relative to the fasting state. Avatrombopag showed dose-proportional pharmacokinetics after single doses from 10 mg (0.25-times the lowest approved dosage) to 80 mg (1.3-times the highest recommended dosage). Healthy subjects administered 40 mg of avatrombopag showed a geometric mean (%CV) maximal concentration (Cmax) of 166 (84%) ng/mL and area under the time-concentration curve, extrapolated to infinity (AUC0-inf) of 4198 (83%) ng.hr/mL. The pharmacokinetics of avatrombopag are similar in both healthy subjects and the chronic liver disease population.
Fecal excretion accounted for 88% of the administered dose, with 34% of the dose excreted as unchanged avatrombopag. Only 6% of the administered dose was found in urine.
Avatrombopag has an estimated mean volume of distribution (%CV) of 180 L (25%).
The mean (%CV) of the clearance of avatrombopag is estimated to be 6.9 L/hr (29%).

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Metabolism / Metabolites
Avatrombopag is primarily metabolized by CYP2C9 and CYP3A4.

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Biological Half-Life
The mean plasma elimination half-life (%CV) of avatrombopag is approximately 19 hours (19%).

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of avatrombopag during breastfeeding. The manufacturer recommends avoiding breastfeeding during the use of avatrombopag and for at least 2 weeks after the last dose.
◉ 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
Avatrombopag is greater than 96% bound to human plasma proteins.

[1]. AKR-501 (YM477) a novel orally-active thrombopoietin receptor agonist. Eur J Haematol. 2009;82(4):247-254.

[2]. Avatrombopag for the treatment of thrombocytopenia in patients with chronic liver disease. Expert Rev Clin Pharmacol. 2019 Sep;12(9):859-865.

[3]. Pharmacokinetic/pharmacodynamic drug-drug interactions of avatrombopag when coadministered with dual or selective CYP2C9 and CYP3A interacting drugs. Br J Clin Pharmacol. 2018;84(5):952-960.

Avatrombopag (Doptelet), is an orally administered, small molecule thrombopoietin receptor (c-Mpl) agonist that increases platelet number without increasing platelet activation, thereby decreasing the need for blood transfusions. Patients with thrombocytopenia and chronic liver disease often require platelet transfusions before surgical procedures to decrease the risk of bleeding. Thrombocytopenia is a common complication in patients suffering from chronic liver disease, occurring as a result of liver disease or a consequence of interferon-based antiviral therapy. Avatrombopag was first approved by the FDA in May 2018 for use in adults with chronic liver disease who are scheduled to undergo a procedure. It is administered orally as the salt form avatrombopag maleate. Doptelet (Avatrombopag) is the first orally administered treatment option for patients with chronic liver disease, allowing a large population of patients to avoid a platelet transfusion before a procedure by increasing platelet counts to the optimal level ≥50,000 per microliter.
Avatrombopag is an orally available platelet thrombopoietin receptor (TPOR; MPL) agonist, with potential megakaryopoiesis stimulating activity. Upon administration, avatrombopag binds to and stimulates TPOR, which may lead to the proliferation and differentiation of megakaryocytes from bone marrow progenitor cells. This increases the production of platelets and may prevent chemotherapy-induced thrombocytopenia (CIT). TPOR is a cytokine receptor and member of the hematopoietin receptor superfamily.
See also: Avatrombopag Maleate (active moiety of).

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Drug Indication
Indicated for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. It is also indicated in adult patients with chronic immune thrombocytopenia who have had an insufficient response to a previous treatment.
FDA Label
Doptelet is indicated for the treatment of severe thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo an invasive procedure. Doptelet is indicated for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients who are refractory to other treatments (e. g. corticosteroids, immunoglobulins).
Treatment of chemotherapy-induced thrombocytopenia

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Mechanism of Action
Avatrombopag is an orally bioavailable, small molecule thrombopoietin (TPO) receptor agonist that stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells resulting in an increased production of platelets. Avatrombopag is not competitive with thrombopoietin for binding to the TPO receptor and has an additive pharmacological effect with TPO on platelet production. Avatrombopag is a thrombopoietin receptor (TPOR; MPL) agonist, with possible megakaryopoiesis stimulating activity. After administration, avatrombopag binds to and stimulates the platelet thrombopoeitin receptor (TPOR), which can lead to the proliferation and differentiation of megakaryocytes from bone marrow progenitor cells. This process increases the production of platelets and may serve to prevent chemotherapy-induced thrombocytopenia (CIT). TPOR is classified as a cytokine receptor and as a member of the hematopoietin receptor superfamily.

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Pharmacodynamics
In a study of efficacy, avatrombopag resulted in dose and exposure-dependent elevations in platelet counts in adults. The onset of the platelet count increase was noted within 3 to 5 days of the start of a 5-day treatment course, with the highest level of effect measured after 10 to 13 days. Following this, platelet counts decreased gradually, returning to near baseline values at the 35-day point. Increased platelet activation leads to increased blood clotting, which may lead to various complications. Avatrombopag does not lead to increased platelet activation.

C29H34CL2N6O3S2

649.65

648.151

570406-98-3

Avatrombopag hydrochloride;570403-17-7;Avatrombopag maleate;677007-74-8

9852519

White to off-white solid powder

1.4±0.1 g/cm3

1.671

6.82

161.87

2

10

7

42

935

0

OFZJKCQENFPZBH-UHFFFAOYSA-N

InChI=1S/C29H34Cl2N6O3S2/c30-20-15-23(41-17-20)24-27(37-12-10-35(11-13-37)21-4-2-1-3-5-21)42-29(33-24)34-26(38)19-14-22(31)25(32-16-19)36-8-6-18(7-9-36)28(39)40/h14-18,21H,1-13H2,(H,39,40)(H,33,34,38)

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)

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)
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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：
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10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
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