p110δ (IC50 = 2.5 nM); p110γ (IC50 = 89 nM); p110β (IC50 = 565 nM); p110α (IC50 = 820 nM); hVps34 (IC50 = 978 nM); DNA-PK (IC50 = 6729 nM)

Idelalisib (CAL-101; GS-1101) 是一种高度选择性和有效的 p110δ 抑制剂 (EC50=8 nM)。虽然在 10 μM 浓度下未发现针对 402 种不同激酶的活性，但针对相关激酶 C2、hVPS34、DNA-PK 和 mTOR 具有更高的选择性（400 至 4000 倍）。 10 μM 时，CAL-101 仅使 PDGF 诱导的 pAkt 降低 25%。 idelalisib (CAL-101) 的 EC50 为 1.9 μM，可抑制 LPA 诱导的 pAkt。 p110γ 的甲酰基-甲硫氨酰-亮氨酰-亮氨酰-苯丙氨酸激活受到抑制，EC50 为 3 μM，而 idelalisib (CAL-101) 则阻断 FcRI p110δ 介导的 CD63 表达，EC50 为 8 nM。因此，在细胞检测中，CAL-101 对 p110δ 的选择性比其他 I 类 PI3K 同工型高 240-2500 倍[1]。 CAL-101 与单独使用载体治疗相比，idelalisib (CAL-101) 诱导慢性淋巴细胞白血病 (CLL) 细胞凋亡显着增加 (P<0.001)。不考虑间期细胞遗传学或 IgVH 突变状态，idelalisib (CAL-101) 在 CLL 细胞中引起选择性细胞毒性[2]。

在 p110D910A/D910A 小鼠和 Idelalisib (CAL-101)（40 mg/kg，静脉注射）治疗后小鼠的脑匀浆中，CD11b+Ly6G+ 中性粒细胞显着减少[3]。

对 CLL 或正常 B 细胞的全细胞裂解物进行 PI3K 测定。有针对 PI3K 的 ELISA 测试。简而言之，将 PI(4,5)P2 底物和含有三磷酸腺苷 (ATP) 的反应缓冲液与全细胞提取物混合，然后将混合物在室温下孵育。添加 PI(3,4,5)P3 检测器与 EDTA（乙二胺四乙酸）并在室温下孵育 1 小时，终止反应。然后将混合物从每个孔转移至 PI3K ELISA 板并再孵育 1 小时。清洗后，将板与辅助检测器一起孵育 30 分钟。第二次洗涤后，向板中加入 3,3',5,5'-四甲基联苯胺溶液 5 分钟，然后加入 H2SO4 以停止所有反应。 Labsystems 的 96 孔板读取器可在 450 nm 处读取板。

进行 MTT 测定以确定细胞毒性。简而言之，将 1×105 个细胞（CLL B 细胞或健康志愿者 T 细胞或 NK 细胞）与不同浓度的 Idelalisib (CAL-101)（0.1 μM、1 μM、5 μM、10 μM）、25 μM 一起孵育 48 小时LY294002，或车辆控制。然后添加MTT试剂。在 Labsystems 读板器中，添加 DMSO 后使用分光光度法在 540 nm 处测量吸光度。膜联蛋白/PI流式细胞术也用于测定不同时间间隔的细胞活力。软件程序Expo-ADC32用于分析数据。对于每个样本，至少计数 10,000 个细胞。结果的表达方式是所有阳性细胞与未处理对照相比的百分比。它与 100 μM Z-VAD 一起用于研究 caspase 依赖性细胞凋亡的实验。添加 1 μg/mL CD40L、800 U/mL IL-4、50 ng/mL BAFF、20 ng/mL TNF-α，或在纤连蛋白或基质（HS-5 细胞系）包被的平板上共培养是一些方法用于研究生存信号的实验。在添加 CLL 细胞之前 24 小时，每个 6 孔板均铺有 75 cm2 烧瓶（80%–100% 汇合），用于基质共培养 [2]。

Mice: For Idelalisib (CAL-101) treatment, wild-type C57BL/6 mice are administered either 40 mg/kg Idelalisib (CAL-101) or vehicle DMSO, by 25 μL infusion into the femoral vein, 15 min before I/R (pre-treatment), or 3 and 6 h after initiation of reperfusion (post-treatment). The cerebral blood flow (CBF) of untreated animals and those given Idelalisib (CAL-101) was measured using a laser Doppler perfusion monitor. An 90-95% reduction in blood flow to the MCAO infarct region was observed in the CBF measurements taken right before and after MCAO, as well as again at 3 h after reperfusion. This reduction was consistent across groups.

Absorption, Distribution and Excretion
Following oral administration, the median Tmax was observed at 1.5 hours.
Following a single dose of 150 mg of [14C] idelalisib, 78% and 14% of the radioactivity was excreted in feces and urine, respectively. GS-563117, idelalisib's major metabolite, accounted for 49% of the radioactivity in the urine and 44% in the feces.
23 L
14.9 L/hr
Following oral administration of a single 150-mg dose of radiolabeled idelalisib, 78% of the dose was recovered in feces and 14% was recovered in urine; GS-563117 accounted for 44% of the dose recovered in feces and 49% of the dose recovered in urine.
The administration of a single dose of Zydelig with a high-fat meal (900 calories: 525 calories fat, 250 calories carboydrates, and 125 calories protein) increased idelalisib AUC 1.4-fold relative to fasting conditions. Zydelig can be administered without regard to food.
The median time to peak concentration (Tmax) was observed at 1.5 hours.

---

Metabolism / Metabolites
Idelalisib is metabolized by aldehyde oxidase and CYP3A to its major metabolite GS-563117, which is inactive against P110δ. Idelalisib is also metabolized to a minor extent by UGT1A4.
Idelalisib, a potent phosphatidylinositol-3-kinase delta (PI3Kd) inhibitor, is metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser extent by cytochrome P450 (CYP) 3A and uridine 5'-diphospho-glucuronosyltransferase 1A4. In vitro, idelalisib inhibits P-glycoprotein (P-gp) and organic anion transporting polypeptides 1B1 and 1B3, and GS-563117 is a time-dependent CYP3A inhibitor. This study enrolled 24 healthy subjects and evaluated (1) the effect of idelalisib on the pharmacokinetics (PK) of digoxin, a P-gp probe substrate, rosuvastatin, a breast cancer resistance protein, and OATP1B1/OATP1B3 substrate, and midazolam, a CYP3A substrate; and (2) the effect of a strong inducer, rifampin, on idelalisib PK. On treatment, the most common clinical adverse events (AEs) were headache and pyrexia. Grade 3 transaminase increases were observed in 5 of 24 subjects and were reversible. Two subjects had serious AEs after treatment completion (grade 3 pyrexia and/or drug-induced liver injury). Idelalisib coadministration did not affect digoxin and rosuvastatin PK. Coadministration with idelalisib increased plasma exposures of midazolam (138% and 437% for maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf), respectively), consistent with the in vitro finding of CYP3A inhibition by GS-563117. Rifampin caused a substantial decrease in idelalisib (58% and 75%, Cmax and AUCinf , respectively) and GS-563117 exposures, indicating an enhanced contribution of CYP3A to idelalisib metabolism under a strongly induced state.
Idelalisib is more than 84% bound to plasma proteins. Idelalisib is metabolized to its major metabolite, GS-563117, principally by cytochrome P-450 (CYP) isoenzyme 3A and aldehyde oxidase; the drug is metabolized only to a minor extent by uridine diphosphate-glucuronosyl transferase (UGT) 1A4.1 GS-563117 is inactive against PI3Kdelta in vitro.
Idelalisib is metabolized via aldehyde oxidase and CYP3A with additional minor metabolism by UGT1A4.

---

Biological Half-Life
The terminal elimination half-life is 8.2 hours.
The mean terminal half-life of idelalisib is 8.2 hours.

Toxicity Summary
IDENTIFICATION AND USE: Idelalisib is a white to off-white powder. It is used as antineoplastic agent, and enzyme inhibitor. It is indicated for the treatment of patients with relapsed chronic lymphocytic leukemia, relapsed follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic lymphoma. HUMAN STUDIES: Idelalisib is an inhibitor of PI3Kdelta kinase, which is expressed in normal and malignant B-cells. Idelalisib induced apoptosis and inhibited proliferation in cell lines derived from malignant B-cells and in primary tumor cells. Treatment of lymphoma cells with idelalisib resulted in inhibition of chemotaxis and adhesion, and reduced cell viability. Severe neutropenia has been reported in 31% of patients receiving idelalisib in clinical studies. Fatal cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have occurred in patients treated with the drug. Fatal and/or serious hepatotoxicity occurred in 18% of patients treated with idelalisib monotherapy and 16% of patients treated with the drug in combinations. Fatal and serious intestinal perforation occurred in treated patients. Severe diarrhea or colitis occurred in 14% of patients treated with idelalisib monotherapy and 20% of patients treated with the drug in combinations. Fatal and serious pneumonitis occurred in patients treated with the drug. Fatal and/or serious infections occurred in 21% of patients treated with idelalisib monotherapy and 48% of patients treated with the drug in combinations. Idelalisib was not clastogenic in the in vitro chromosome aberration assay using human peripheral blood lymphocytes. ANIMAL STUDIES: Idelalisib was not carcinogenic in a 26-week study in transgenic mice when administered daily by oral gavage at doses up to 500 mg/kg/day in males and 1000 mg/kg/day in females. Idelalisib was not carcinogenic in a 2-year study in rats when administered daily by oral gavage. In an embryo-fetal development study in rats, pregnant animals receiving oral doses of idelalisib during the period of organogenesis (implantation to closure of the hard palate), embryo-fetal toxicities were observed at the mid- and high-doses that also resulted in maternal toxicity, based on reductions in maternal body weight gain. Adverse findings at idelalisib doses of 75 mg/kg/day included decreased fetal weights, external malformations (short tail), and skeletal variations (delayed ossification and/or unossification of the skull, vertebrae, and sternebrae). Additional findings were observed at 150 mg/kg/day dose of idelalisib and included urogenital blood loss, complete resorption, increased post-implantation loss, and malformations (vertebral agenesis with anury, hydrocephaly, and microphthalmia/anophthalmia). In a separate fertility study, treated female rats (25, 50, or 100 mg/kg/day of idelalisib) were mated with untreated males. There were no adverse effects on fertility parameters; however, there was a decrease in the number of live embryos at the high dose. Idelalisib did not induce mutations in the bacterial mutagenesis (Ames) assay. Idelalisib was genotoxic in males in the in vivo rat micronucleus study at a high dose of 2000 mg/kg.

---

Hepatotoxicity
In clinical trials of idelalisib combined with rituximab in patients with CLL and lymphoma, the rates of serum enzyme elevations during therapy ranged from 25% to 35% and were above 5 times the ULN in 5% to 8% (compared to 1% with placebo and rituximab). Severe instances of severe acute hepatocellular injury and acute liver failure were reported in patients receiving idelalisib alone and with rituximab, but the clinical features of the cases were not be described in detail. Serum enzyme elevations typically arose within 4 to 12 weeks of starting therapy and usually resolved rapidly with temporary discontinuation. In some instances, however, serum aminotransferases remained high despite stopping therapy, and in this situation corticosteroids appeared to have a beneficial effect. Most patients who developed significant serum enzyme elevations with idelalisib had a rapid recurrence upon rechallenge. In patients receiving corticosteroids, however, recurrence was less common and generally mild, allowing for restarting of therapy in many patients. Thus, idelalisib is a frequent cause of acute hepatocellular injury which may have an autoimmune component. Because of its many serious adverse events and limited efficacy in comparison to other agents, idelalisib has not been widely used and it potential for causing acute clinically apparent liver injury with jaundice has not been well defined.
Because, idelalisib affects B cell function, it may also be capable of inducing reactivation of hepatitis B, although in published trials of the agent, reactivation was not reported.
Likelihood score: D (possible cause of clinically apparent liver injury).

---

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of idelalisib during breastfeeding. Because idelalisib is more than 84% bound to plasma proteins, the amount in milk is likely to be low. It is sometimes given in combination with rituximab, which may increase the risk to the infant. The manufacturer recommends that breastfeeding be discontinued during idelalisib therapy and for at least 1 month 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.

---

Protein Binding
Idelalisib is greater than 84% bound to human plasma proteins with no concentration dependence.

---

Interactions
Fatal and/or serious hepatotoxicity occurred in 18% of patients treated with Zydelig monotherapy and 16% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies.
Idelalisib, a potent phosphatidylinositol-3-kinase delta (PI3Kd) inhibitor, is metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser extent by cytochrome P450 (CYP) 3A and uridine 5'-diphospho-glucuronosyltransferase 1A4. In vitro, idelalisib inhibits P-glycoprotein (P-gp) and organic anion transporting polypeptides 1B1 and 1B3, and GS-563117 is a time-dependent CYP3A inhibitor. This study enrolled 24 healthy subjects and evaluated (1) the effect of idelalisib on the pharmacokinetics (PK) of digoxin, a P-gp probe substrate, rosuvastatin, a breast cancer resistance protein, and OATP1B1/OATP1B3 substrate, and midazolam, a CYP3A substrate; and (2) the effect of a strong inducer, rifampin, on idelalisib PK. On treatment, the most common clinical adverse events (AEs) were headache and pyrexia. Grade 3 transaminase increases were observed in 5 of 24 subjects and were reversible. Two subjects had serious AEs after treatment completion (grade 3 pyrexia and/or drug-induced liver injury). Idelalisib coadministration did not affect digoxin and rosuvastatin PK. Coadministration with idelalisib increased plasma exposures of midazolam (138% and 437% for maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf), respectively), consistent with the in vitro finding of CYP3A inhibition by GS-563117. Rifampin caused a substantial decrease in idelalisib (58% and 75%, Cmax and AUCinf , respectively) and GS-563117 exposures, indicating an enhanced contribution of CYP3A to idelalisib metabolism under a strongly induced state.
Idelalisib is approved for the treatment of relapsed chronic lymphocytic leukemia together with Rituximab and for monotherapy of follicular B-cell non-Hodgkin's lymphoma and small lymphocytic lymphoma. It is a potent and selective phosphatidylinositol 3-kinase-d (PI3K-d) inhibitor. PI3K-d primarily is expressed in B-cells and prevents effectively proliferation in malignant B-cells. We provide a detailed report on treatment history and photo documentation of acute adverse effects of radiation therapy with simultaneous Idelalisib medication in one case of B-CLL. Radiosensitivity tests were performed for the index patient under Idelalisib and after the addition of Idelalisib to healthy individuals' blood. Radiosensitivity in human lymphocytes was analyzed with a three color in situ hybridization assay. Primary skin fibroblasts were studied after a treatment with Idelalisib for apoptosis, necrosis and cell cycle using flow cytometry. DNA double-strand break repair was analyzed by gammaH2AX immunostaining. The index patient presented a strong grade 2 radiodermatitis and grade 3 mucositis after irradiation with 20 Gy and a simultaneous intake of Idelalisib. Irradiations without Idelalisib medication were well tolerated and resulted in not more than grade 1 radiodermatitis. The index patient under Idelalisib had a radiosensitivity of 0.62 B/M which is in the range of clearly radiosensitive patients. A combined treatment of lymphocytes with 2 Gy and 10 nmol/L Idelalisib showed a tendency to an increased radiosensitivity. We found a clear increase of apoptosis as a result of the combined treatment in the Idelalisib dose range of 1 to 100 nmol/L compared to solely irradiated cells or solely Idelalisib treated cells (p=0.05). A combined Idelalisib radiotherapy treatment has an increased risk of side effects. However, combined therapy seems to be feasible when patients are monitored closely.
Concomitant use of idelalisib with an inducer of P-gp may result in decreased systemic exposure to idelalisib. When the potent CYP3A and P-gp inducer rifampin was administered concomitantly with idelalisib, systemic exposure to idelalisib was decreased.
For more Interactions (Complete) data for Idelalisib (8 total), please visit the HSDB record page.

[1]. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood, 2011, 117(2), 591-594.

[2]. Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood, 2010, 116(12), 2078-2088.

[3]. PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model. Nat Commun. 2014 Mar 14;5:3450.

[4]. Synergistic targeting of the regulatory and catalytic subunits of PI3Kδ in mature B cell malignancies. Clin Cancer Res. 2018 Mar 1;24(5):1103-1113.

Therapeutic Uses
Antineoplastic Agents; Enzyme Inhibitors
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Idelalisib is included in the database.
Zydelig is indicated, in combination with rituximab, for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) for whom rituximab alone would be considered appropriate therapy due to other co-morbidities. /Included in US product label/
Zydelig is indicated for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma (FL) who have received at least two prior systemic therapies. Accelerated approval was granted for this indication based on Overall Response Rat. An improvement in patient survival or disease related symptoms has not been established. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials. /Included in US product label/
Zydelig is indicated for the treatment of patients with relapsed small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies. /Included in US product label/

---

Drug Warnings
/BOXED WARNING/ WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC. Fatal and/or serious hepatotoxicity occurred in 16% to 18% of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig as recommended.
/BOXED WARNING/ WARNING: FATAL AND SERIOUS TOXICITIES: SEVERE DIARRHEA, COLITIS. Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 20% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig as recommended.
/BOXED WARNING/ WARNING: FATAL AND SERIOUS TOXICITIES: PNEUMONITIS. Fatal and/or serious pneumonitis occurred in 4% of Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig as recommended.
/BOXED WARNING/ WARNING: FATAL AND SERIOUS TOXICITIES: INFECTIONS. Fatal and/or serious infections occurred in 21% to 48% of Zydelig-treated patients. Monitor for signs and symptoms of infection. Interrupt Zydelig if infection is suspected.
For more Drug Warnings (Complete) data for Idelalisib (20 total), please visit the HSDB record page.

C22H18FN7O

415.42

415.155

C, 63.61; H, 4.37; F, 4.57; N, 23.60; O, 3.85

870281-82-6

Idelalisib-d5;1830330-31-8

11625818

white solid powder

1.5±0.1 g/cm3

1.741

2.96

101.38

2

7

5

31

685

1

[C@@H](C1=NC2C=CC=C(C=2C(=O)N1C1C=CC=CC=1)F)(CC)NC1=NC=NC2N=CNC1=2

IFSDAJWBUCMOAH-HNNXBMFYSA-N

InChI=1S/C22H18FN7O/c1-2-15(28-20-18-19(25-11-24-18)26-12-27-20)21-29-16-10-6-9-14(23)17(16)22(31)30(21)13-7-4-3-5-8-13/h3-12,15H,2H2,1H3,(H2,24,25,26,27,28)/t15-/m0/s1

(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one

GS1101; CAL-101; GS 1101; CAL101; GS-1101; CAL 101; Idelalisib; trade name Zydelig

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.02 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 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 2 中的溶解度: ≥ 2.5 mg/mL (6.02 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。

---

View More

配方 3 中的溶解度: ≥ 2.5 mg/mL (6.02 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 储备液添加到 900 μL 玉米油中并混合均匀。

---

配方 4 中的溶解度: 30%PEG 400 (dissolve first)+0.5% Tween 80 +5% Propylene glycol : 30mg/mL

---

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。