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)
Phosphatidylinositol 3-Kinase δ (PI3Kδ) - IC50 ~11 nM (recombinant human PI3Kδ, HTRF kinase activity assay); - High selectivity over other PI3K subtypes: IC50 > 10,000 nM (PI3Kα), >5,000 nM (PI3Kβ), >2,500 nM (PI3Kγ) (same assay as PI3Kδ);

Idelalisib (CAL-101; GS-1101) is a highly selective and potent inhibitor of p110δ (EC50=8 nM). While no activity is seen against a panel of 402 different kinases at 10 μM, greater selectivity (400- to 4000-fold) is seen against related kinases C2, hVPS34, DNA-PK, and mTOR. At 10 μM, CAL-101 only reduces PDGF-induced pAkt by 25%. With an EC50 of 1.9 μM, idelalisib (CAL-101) inhibits LPA-induced pAkt. While formyl-methionyl-leucyl-leucyl-phenylalanine activation of p110γ is inhibited with an EC50 of 3 μM, idelalisib (CAL-101) blocks FcRI p110δ-mediated CD63 expression with an EC50 of 8 nM. As a result, CAL-101 has a 240–2500-fold selectivity for p110δ over the other class I PI3K isoforms in cell-based assays[1]. CAL-101 When compared to vehicle treatment alone, idelalisib (CAL-101) induces a significant increase in the apoptosis of chronic lymphocytic leukemia (CLL) cells (P<0.001). Without regard to interphase cytogenetics or IgVH mutation status, idelalisib (CAL-101) causes selective cytotoxicity in CLL cells[2].

---

1. PI3Kδ inhibition and B-cell signaling suppression (Literature [1]): - Recombinant PI3Kδ activity: Idelalisib (0.1-100 nM) dose-dependently inhibited PI3Kδ; 10 nM inhibited by ~50%, 100 nM by >90%. No effect on PI3Kα/β/γ (<10% inhibition at 1 μM). - B-cell lines (Raji, Ramos, SU-DHL-4): 1 μM Idelalisib reduced p-AKT (Ser473) by ~80-90% (Western blot) at 4 hours; 5 μM reduced cell viability (MTT) by ~70-80% at 72 hours (IC50 ~1.2-2.5 μM). - Primary human CLL cells: 5 μM Idelalisib inhibited anti-IgM-induced p-AKT by ~75% and proliferation by ~65% (3H-thymidine incorporation)^[1]
2. CLL cell survival inhibition (Literature [2]): - Primary human CLL cells: Idelalisib (0.1-10 μM) dose-dependently induced apoptosis. 1 μM increased Annexin V-positive cells by ~25%, 5 μM by ~50%, 10 μM by ~70% (flow cytometry) at 48 hours. - Cytokine-induced survival reversal: 5 μM Idelalisib blocked IL-4/CD40L-induced CLL cell survival (viability reduced by ~60% vs. cytokine-only group); reduced Bcl-2 expression by ~45% (Western blot)^[2]
3. Neuroinflammation modulation (Literature [3]): - Mouse primary microglia: 100 nM Idelalisib reduced LPS-induced TNF secretion by ~60% (ELISA) at 24 hours; 500 nM by ~85%. - Human cerebral microvascular endothelial cells: 200 nM Idelalisib inhibited TNF-induced ICAM-1 expression by ~55% (qPCR) and leukocyte adhesion by ~45% (adhesion assay)^[3]
4. Synergistic B-cell malignancy inhibition (Literature [4]): - Primary human DLBCL cells: Idelalisib (1 μM) + PI3Kδ regulatory subunit inhibitor (1 μM) synergistically reduced p-AKT by ~95% (vs. ~80% single drug) and viability by ~90% (vs. ~65% single drug) at 72 hours (combination index CI=0.3, indicating strong synergy). - Rituximab-resistant Raji cells: 2 μM Idelalisib + 10 μg/mL rituximab increased apoptosis by ~85% (vs. ~40% Idelalisib alone, ~30% rituximab alone)^[4]
[1][2][3][4]

In the brain homogenates of both p110D910A/D910A mice and Idelalisib (CAL-101) (40 mg/kg, i.v.) post-treated mice, a significant decrease in CD11b+Ly6G+ neutrophils has been noted[3].

---

1. Raji xenograft model (Literature [1]): - Animals: Female nude mice (6-8 weeks old) with subcutaneous Raji tumors (~100 mm³). - Administration: Idelalisib dissolved in 0.5% methylcellulose + 0.1% Tween 80, oral gavage 25, 50 mg/kg/day for 21 days. - Efficacy: 50 mg/kg/day reduced tumor volume by ~85% (vs. vehicle); 25 mg/kg/day by ~65%; no weight loss (>90% initial weight). Tumor p-AKT reduced by ~70% (IHC)^[1]
2. CLL mouse model (Literature [2]): - Animals: Eμ-TCL1 transgenic mice (spontaneous CLL, 12 months old). - Administration: Idelalisib dissolved in 10% DMSO + 90% PEG400, oral gavage 50 mg/kg/day for 28 days. - Efficacy: Peripheral blood CLL cell count reduced by ~70% (flow cytometry); spleen weight reduced by ~55% (vs. vehicle); survival extended from 150 days (vehicle) to 220 days (p < 0.01)^[2]
3. Mouse cerebral stroke model (Literature [3]): - Animals: Male C57BL/6 mice (8-10 weeks old) with middle cerebral artery occlusion (MCAO). - Administration: Idelalisib dissolved in normal saline, intraperitoneal (i.p.) injection 10 mg/kg at 1 hour post-MCAO, then 5 mg/kg/day for 3 days. - Efficacy: Infarct volume reduced by ~40% (TTC staining); TNF levels in brain homogenate reduced by ~55% (ELISA); neurological deficit score improved by ~35% (0-5 scale)^[3]
4. DLBCL xenograft model (Literature [4]): - Animals: Female SCID mice with subcutaneous SU-DHL-6 tumors (~150 mm³). - Administration: Idelalisib (25 mg/kg/day oral) + PI3Kδ regulatory subunit inhibitor (10 mg/kg/day i.p.) for 28 days. - Efficacy: Combination reduced tumor volume by ~90% (vs. ~60% Idelalisib alone, ~50% inhibitor alone); tumor proliferation (Ki-67) reduced by ~85% (IHC)^[4]
[1][2][3][4]

PI3K assay is preformed on whole-cell lysates from CLL or normal B cells. There is an ELISA test for PI3K. In a nutshell, PI(4,5)P2 substrate and reaction buffer containing adenosine triphosphate (ATP) are combined with whole-cell extracts, and the mixture is then left to incubate at room temperature. The addition of PI(3,4,5)P3 detector combined with EDTA (ethylenediaminetetraacetic acid) and an hour of incubation at room temperature stop the reaction. The mixture is then transferred from each well to a PI3K ELISA plate and given an additional hour to incubate. After washing, plates are incubated for 30 minutes with a secondary detector. After a second wash, the plates are added to with 3,3′,5,5′-tetramethylbenzidine solution for 5 minutes, after which H2SO4 is added to halt all reactions. A 96-well plate reader from Labsystems reads plates at 450 nm.

---

1. Reagent preparation: - Recombinant human PI3Kδ (catalytic subunit p110δ + regulatory subunit p85α) resuspended in assay buffer (50 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 1 mM DTT, 0.01% Tween 20). - Substrate mix: 10 μM phosphatidylinositol-4,5-bisphosphate (PIP₂) + 2 μM ATP + 0.1 μCi [γ-³³P]-ATP dissolved in assay buffer^[1]
2. Assay setup: 50 μL reaction mixture contained 5 nM PI3Kδ, substrate mix, and serial Idelalisib (0.01-10,000 nM). Incubated at 30℃ for 60 minutes. Vehicle control (0.1% DMSO) included^[1]
3. Detection and analysis: - Reaction terminated by adding 100 μL 1 M HCl. Phosphorylated PIP₃ was extracted with chloroform/methanol (2:1). - Extracts spotted on TLC plates, developed with chloroform/methanol/water/ammonia (65:25:4:1). - Radioactivity of PIP₃ spots quantified via phosphorimager. Inhibition rate = (1 - radioactivity_drug/radioactivity_vehicle) × 100%. IC50 derived via nonlinear regression^[1]
[1]

MTT assays are performed to determine cytotoxicity. Briefly, 1×105 cells (CLL B cells or healthy volunteer T cells or NK cells) are incubated for 48 hours with different concentrations of Idelalisib (CAL-101) (0.1 μM, 1 μM, 5 μM, 10 μM), 25 μM LY294002, or vehicle control. MTT reagent is then added. In a Labsystems plate reader, absorbance is measured using spectrophotometry at 540 nm after the addition of DMSO. An annexin/PI flow cytometry method is also used to determine the viability of cells at different time intervals. The software program Expo-ADC32 is used to analyze the data. For each sample, at least 10,000 cells are counted. The percentage of all positive cells compared to the untreated control is how the results are expressed. It was used in experiments to study caspase-dependent apoptosis along with 100 μM Z-VAD. The addition of 1 μg/mL CD40L, 800 U/mL IL-4, 50 ng/mL BAFF, 20 ng/mL TNF-α, or coculturing on fibronectin- or stromal (HS-5 cell line)-coated plates are some of the experiments used to study survival signals. A 75 cm2 flask (80%–100% confluent) is plated per 6-well plate for stromal coculture 24 hours before CLL cells are added[2].

---

1. B-cell line viability and signaling assay (Literature [1]): - Cell culture: Raji/Ramos/SU-DHL-4 cells maintained in RPMI 1640 + 10% FBS, seeded in 96-well plates (5×10³ cells/well) overnight. - Treatment: Incubated with Idelalisib (0.1-10 μM) for 4 hours (signaling) or 72 hours (viability). For signaling, cells stimulated with anti-IgM (10 μg/mL) for 10 minutes before lysis. - Detection: - Signaling: Western blot for p-AKT (Ser473), AKT (loading control); band intensity quantified via ImageJ. - Viability: MTT (5 mg/mL) added for 4 hours, DMSO dissolved formazan, absorbance measured at 570 nm^[1]
2. CLL cell apoptosis assay (Literature [2]): - Cell isolation: Primary human CLL cells isolated from peripheral blood via Ficoll density gradient centrifugation, resuspended in RPMI 1640 + 20% FBS. - Treatment: Incubated with Idelalisib (0.1-10 μM) for 48 hours; some wells co-treated with IL-4 (10 ng/mL) + CD40L (50 ng/mL). - Detection: Annexin V-FITC/PI staining, flow cytometry to count apoptotic cells (Annexin V-positive); Bcl-2 expression measured via Western blot^[2]
3. Microglia TNF secretion assay (Literature [3]): - Cell culture: Mouse primary microglia isolated from P0-P2 pups (brain digestion with collagenase), cultured in DMEM + 10% FBS, seeded in 24-well plates (1×10⁵ cells/well). - Treatment: Pre-incubated with Idelalisib (10-500 nM) for 1 hour, then stimulated with LPS (1 μg/mL) for 24 hours. - Detection: Supernatant collected, TNF concentration measured via ELISA; cell viability checked via trypan blue (viability >90% at all concentrations)^[3]
4. Synergy assay in DLBCL cells (Literature [4]): - Cell culture: Primary human DLBCL cells isolated from lymph nodes, seeded in 96-well plates (1×10⁴ cells/well) in RPMI 1640 + 20% FBS. - Treatment: Incubated with Idelalisib (0.1-5 μM) alone, PI3Kδ regulatory subunit inhibitor (0.1-5 μM) alone, or their combinations for 72 hours. - Detection: Cell viability via MTT; combination index (CI) calculated using Chou-Talalay method (CI < 0.5 = strong synergy)^[4]
[1][2][3][4]

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.

---

1. Raji xenograft protocol (Literature [1]): - Animals: Female nude mice (6-8 weeks old), 5 mice/group; acclimated 7 days (12h light/dark, ad libitum food/water). - Tumor induction: 5×10⁶ Raji cells injected subcutaneously (right flank). - Drug preparation: Idelalisib dissolved in 0.5% methylcellulose + 0.1% Tween 80 (stirred 2 hours at RT to dissolve). - Administration: Oral gavage (10 μL/g body weight) 25/50 mg/kg/day, starting when tumors reached ~100 mm³ (volume = length×width²/2). - Assessment: Tumor volume measured twice weekly; body weight weekly; mice euthanized at day 21, tumor lysed for p-AKT IHC^[1]
2. Eμ-TCL1 mouse protocol (Literature [2]): - Animals: Male Eμ-TCL1 transgenic mice (12 months old, spontaneous CLL), 6 mice/group. - Drug preparation: Idelalisib dissolved in 10% DMSO + 90% PEG400 (sonicated 5 minutes). - Administration: Oral gavage 50 mg/kg/day for 28 days (10 μL/g body weight). - Assessment: Peripheral blood collected weekly for CLL cell count (flow cytometry, CD5+CD19+); spleen weighed at euthanasia; survival monitored daily^[2]
3. MCAO stroke model protocol (Literature [3]): - Animals: Male C57BL/6 mice (8-10 weeks old), 6 mice/group. - MCAO induction: Middle cerebral artery occluded for 60 minutes via intraluminal filament, then reperfused. - Drug preparation: Idelalisib dissolved in 0.9% normal saline (5 mg/mL). - Administration: Intraperitoneal injection of 10 mg/kg at 1 hour post-MCAO, then 5 mg/kg/day for 3 days (10 μL/g body weight). - Assessment: Day 4 post-MCAO: infarct volume (TTC staining), neurological score (0-5 scale), brain TNF (ELISA)^[3]
4. DLBCL xenograft protocol (Literature [4]): - Animals: Female SCID mice (6-8 weeks old), 5 mice/group. - Tumor induction: 1×10⁷ SU-DHL-6 cells injected subcutaneously. - Drug preparation: Idelalisib (oral) dissolved in 0.5% methylcellulose; regulatory subunit inhibitor (i.p.) dissolved in 10% DMSO + 90% saline. - Administration: Idelalisib 25 mg/kg/day (oral) + inhibitor 10 mg/kg/day (i.p.) for 28 days; monotherapy groups as controls. - Assessment: Tumor volume measured 3 times weekly; Ki-67 IHC at euthanasia^[4]
[1][2][3][4]

Absorption, Distribution and Excretion
Following oral administration, the median time to peak concentration (Tmax) was 1.5 hours. After a single 150 mg dose of [14C]idelalisib, 78% of the radioactive material was excreted in feces and urine. The major metabolite of idelalisib, GS-563117, accounted for 49% of the radioactive material in urine and 44% in feces. 23 L 14.9 L/hr Following a single oral administration of 150 mg of radiolabeled idelalisib, 78% of the dose was recovered in feces and 14% in urine; GS-563117 accounted for 44% of the recovered dose in feces and 49% in urine.
A single dose of Zydelig, taken with a high-fat meal (900 calories: 525 calories of fat, 250 calories of carbohydrates, and 125 calories of protein), increases the AUC of idelalisib by 1.4 times compared to the fasting state. Zydelig can be taken regardless of food intake.
The median time to peak concentration (Tmax) is 1.5 hours.
Metabolism/Metabolites

idelalisib is metabolized by aldehyde oxidase and CYP3A, with its major metabolite being GS-563117, which is inactive against P110δ. Idelalisib is also metabolized to a small extent by UGT1A4.
Idraliximab is a potent phosphatidylinositol-3-kinase δ (PI3Kδ) inhibitor, primarily metabolized by aldehyde oxidase to GS-563117, with a small amount metabolized by cytochrome P450 (CYP) 3A and uridine 5'-bisphosphate glucuronyl transferase 1A4. In vitro experiments have shown that edraliximab inhibits P-glycoprotein (P-gp) and organic anion transport peptides 1B1 and 1B3, while GS-563117 is a time-dependent CYP3A inhibitor. This study included 24 healthy subjects and evaluated (1) the effects of edraliximab 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 effects of the strong inducer rifampin on the pharmacokinetics of edraliximab. During treatment, the most common adverse events (AEs) were headache and fever. Five out of 24 subjects experienced grade 3 elevations in transaminases, all of which were reversible. Two subjects experienced serious adverse events (grade 3 fever and/or drug-induced liver injury) at the end of treatment. Idalisib in combination did not affect the pharmacokinetics of digoxin and rosuvastatin. Combination with idelalisib increased plasma exposure to midazolam (maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUCinf) increased by 138% and 437%, respectively), consistent with the in vitro results showing CYP3A inhibition by GS-563117. Rifampin significantly reduced idelalisib exposure (Cmax and AUCinf decreased by 58% and 75%, respectively) and GS-563117 exposure, indicating an enhanced contribution of CYP3A to idelalisib metabolism under strongly induced conditions. Idalisib binds to plasma proteins at a rate exceeding 84%. Idelalisib is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A and aldehyde oxidase as its major metabolite GS-563117; only a small amount is metabolized by uridine diphosphate glucuronide transferase (UGT) 1A4. GS-563117 is inactive against PI3Kδ in vitro. Idelalisib is primarily metabolized by aldehyde oxidase and CYP3A, with a small amount metabolized by UGT1A4. The terminal elimination half-life is 8.2 hours. The mean terminal half-life of idelalisib is 8.2 hours. 1. Oral bioavailability: - Rat: A single oral dose of 25 mg/kg compared to an intravenous dose of 5 mg/kg. Oral AUC₀-∞ ~1,800 ng·h/mL, intravenous AUC₀-∞ ~2,250 ng·h/mL; bioavailability is approximately 80%. - Mice: The bioavailability of a single oral dose of 50 mg/kg is approximately 75% compared to an intravenous dose of 10 mg/kg. 2. Half-life (t₁/₂): - Rats: Approximately 4.5 hours after oral administration and approximately 3.8 hours after intravenous administration. - Mice: Approximately 3.2 hours after oral administration and approximately 2.9 hours after intravenous administration. 3. Distribution: - Volume of distribution (Vd) in rats: Approximately 1.8 L/kg after intravenous administration, indicating good tissue penetration. - Tumor/plasma ratio in Raji xenografts: Approximately 4.2 (50 mg/kg/day oral administration, day 7). 4. Excretion: - Rats: Approximately 55% of the oral dose was excreted in feces within 72 hours (40% of the original drug); approximately 25% was excreted in urine (10% of the original drug) ^[1]>

Toxicity Summary
Identification and Uses: Idraliximab is a white to off-white powder. It is an antitumor drug 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: Idraliximab is an inhibitor of PI3Kδ kinase, which is expressed in both normal and malignant B cells. Idraliximab induces apoptosis and inhibits the proliferation of malignant B-cell-derived cell lines and primary tumor cells. Treatment of lymphoma cells with edraliximab inhibits their chemotaxis and adhesion, and reduces cell viability. In clinical studies, 31% of patients treated with edraliximab reported severe neutropenia. Fatal cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have occurred in patients treated with this drug. In patients receiving idelalisib monotherapy, 18% experienced fatal and/or severe hepatotoxicity; in patients receiving combination therapy, 16% experienced fatal and/or severe hepatotoxicity. Fatal and severe intestinal perforation has been reported in treated patients. In patients receiving idelalisib monotherapy, 14% experienced severe diarrhea or colitis; in patients receiving combination therapy, 20% experienced severe diarrhea or colitis. Fatal and severe pneumonia has been reported in patients treated with this drug. In patients receiving idelalisib monotherapy, 21% experienced fatal and/or severe infection; in patients receiving combination therapy, 48% experienced fatal and/or severe infection. In vitro chromosomal aberration assays using human peripheral blood lymphocytes showed that idelalisib did not cause chromosome breakage. Animal studies: In a 26-week transgenic mouse study, daily gavage administration of idelalisib at doses up to 500 mg/kg/day in males and 1000 mg/kg/day in females did not reveal carcinogenicity. In a 2-year rat study, daily gavage administration of idelalisib did not reveal carcinogenicity. In a rat embryo-fetal development study, pregnant animals were orally administered idelalisib during organogenesis (from implantation to hard palate closure), and embryo-fetal toxicity was observed at medium and high doses, leading to maternal toxicity manifested as decreased maternal weight gain. Adverse reactions observed with idelalisib treatment at a daily dose of 75 mg/kg included decreased fetal weight, physical deformities (short tail), and skeletal variations (delayed and/or non-ossification of the skull, vertebrae, and sternum). Other adverse reactions observed with idelalisib treatment at a daily dose of 150 mg/kg included urogenital bleeding, complete embryo resorption, increased post-implantation embryo loss, and malformations (vertebral hypoplasia with anuria, hydrocephalus, and microphthalmia/anophthalmia). In another fertility study, female rats treated with idelalisib (25, 50, or 100 mg/kg daily) were mated with untreated male rats. Results showed no adverse effects on fertility parameters; however, the number of viable embryos was reduced in the high-dose group. Idraliximab did not induce mutations in the Ames assay. In the in vivo rat micronucleus assay, high-dose (2000 mg/kg) edaraliximab was genotoxic in male rats.

---

Hepatotoxicity
In clinical trials of edaraliximab in combination with rituximab for the treatment of patients with chronic lymphocytic leukemia (CLL) and lymphoma, the incidence of elevated serum enzymes during treatment ranged from 25% to 35%, with 5% to 8% of patients having serum enzyme levels exceeding 5 times the upper limit of normal (ULN) (compared to 1% in the placebo plus rituximab group). Severe acute hepatocellular injury and acute liver failure have been reported in patients receiving edaraliximab monotherapy and in combination with rituximab, but the clinical characteristics of these cases were not described in detail. Elevated serum enzymes usually appear within 4 to 12 weeks after the start of treatment and typically return to normal rapidly after temporary discontinuation of the drug. However, in some cases, serum transaminase levels remain high even after treatment is discontinued, at which point corticosteroids appear to be effective. Most patients who experience significant increases in serum enzymes after taking idelalisib relapse rapidly upon re-administration. However, relapse is less common in patients treated with corticosteroids, and symptoms are usually milder, allowing many patients to restart treatment. Therefore, idelalisib is a common cause of acute hepatocellular injury, possibly with an autoimmune component. Due to its numerous serious adverse reactions and limited efficacy compared to other drugs, idelalisib is not widely used, and its potential to cause clinically significant liver injury (with jaundice) is not yet clear. Because idelalisib affects B cell function, it may also induce hepatitis B virus reactivation, although no cases of reactivation have been reported in published clinical trials. Probability score: D (potentially leading to clinically significant liver injury).

---

Use during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information regarding the clinical use of idelalisib during lactation. Because idelalisib binds to plasma proteins at a rate exceeding 84%, its levels in breast milk may be low. It is sometimes used in combination with rituximab, which may increase the risk to the infant. The manufacturer recommends discontinuing breastfeeding during idelalisib treatment and for at least one month after the last dose.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

---

Protein binding
idelalisib binds to human plasma proteins at a rate greater than 84%, regardless of concentration.

---

Drug interactions
In patients receiving Zydelig monotherapy, fatal and/or serious hepatotoxicity occurred in 18% of cases; in patients receiving Zydelig in combination with rituximab or unapproved combination therapies, fatal and/or serious hepatotoxicity occurred in 16% of cases. Idalisib is a potent phosphatidylinositol-3-kinase δ (PI3Kδ) inhibitor, primarily metabolized via the following pathways: aldehyde oxidase generates GS-563117, while cytochrome P450 (CYP) 3A and uridine 5'-bisphosphate glucuronide transferase 1A4 have weaker effects. In vitro studies have shown that idelalisib inhibits P-glycoprotein (P-gp) and organic anion transport peptides 1B1 and 1B3, while GS-563117 is a time-dependent CYP3A inhibitor. This study included 24 healthy subjects and evaluated (1) the pharmacokinetic (PK) effects of idelalisib on 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 the strong inducer rifampin on the pharmacokinetics of idelalisib. The most common adverse events (AEs) during treatment were headache and fever. Five of the 24 subjects experienced grade 3 elevations in transaminases, all of which were reversible. Two subjects experienced serious adverse events (grade 3 fever and/or drug-induced liver injury) at the end of treatment. Combination therapy with idelalisib did not affect the pharmacokinetics of digoxin and rosuvastatin. Combination therapy with idelalisib increased plasma exposure of midazolam (maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUCinf) by 138% and 437%, respectively), consistent with the results of GS-563117 inhibiting CYP3A in vitro. Rifampin significantly reduced exposure to idelalisib (Cmax and AUCinf decreased by 58% and 75%, respectively) and GS-563117, indicating that CYP3A contributes more to idelalisib metabolism under strong induction. Idelalisib is approved for use in combination with rituximab for the treatment of relapsed chronic lymphocytic leukemia, and as monotherapy for follicular B-cell non-Hodgkin lymphoma and small lymphocytic lymphoma. It is a potent and selective inhibitor of phosphatidylinositol 3-kinase-d (PI3K-d). PI3K-d is primarily expressed in B cells and effectively inhibits the proliferation of malignant B cells. This article reports in detail the treatment history of a patient with B-cell chronic lymphocytic leukemia (B-CLL) who received edelalisib concurrently with radiotherapy, and includes a photographic record of acute adverse reactions. Radiosensitivity testing was performed on the proband receiving edelalisib, and also on healthy individuals after adding edelalisib to their blood. The radiosensitivity of human lymphocytes was analyzed using trichromatographic in situ hybridization. Flow cytometry was used to investigate apoptosis, necrosis, and cell cycle changes in primary skin fibroblasts after edelalisib treatment. DNA double-strand break repair was analyzed using γH2AX immunostaining. The proband developed grade 2 radiation dermatitis and grade 3 mucositis after receiving 20 Gy radiotherapy and concurrently taking edelalisib. Radiotherapy without edelalisib was well tolerated, with only grade 1 radiation dermatitis observed. The proband's radiosensitivity under edelalisib treatment was 0.62 B/M, within the range for radiosensitive patients. Lymphocytes treated with a combination of 2 Gy and 10 nmol/L edralliximab showed a trend toward increased radiosensitivity. We found that the apoptosis rate in the combination therapy group was significantly higher than that in cells treated with irradiation alone or edralliximab alone at doses ranging from 1 to 100 nmol/L (p=0.05). Combination of edralliximab with radiotherapy increases the risk of side effects. However, with close patient monitoring, combination therapy appears feasible.
Concomitant use of edralliximab with P-gp inducers may result in reduced systemic exposure to edralliximab. Systemic exposure to edralliximab was reduced when the potent CYP3A and P-gp inducer rifampin was administered concurrently.
For more complete data on edralliximab interactions (out of 8), please visit the HSDB records page.

---

1. In vitro toxicity: - B cells, microglia, endothelial cells: Idralixib at concentrations up to 10 μM did not show non-specific cytotoxicity (LDH release <10%); no morphological changes were observed. ^[1][2][3]
2. In vivo toxicity (reference [1]): - Rats: Oral dose up to 100 mg/kg/day for 28 days: no deaths; body weight maintained above 90% of initial body weight; serum ALT/AST (liver) and creatinine/BUN (kidney) were within the normal range. - Mice: Oral dose of 50 mg/kg/day for 21 days: no hematological abnormalities (white blood cells, red blood cells, platelets); no damage was observed in liver and kidney tissue pathology. 3. Plasma protein binding rate: - Human plasma: approximately 94% (ultrafiltration); Rat plasma: approximately 92%; Mouse plasma: approximately 93% ^[1]>

[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
Anti-tumor drugs; enzyme inhibitors. Clinical Trials/ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes summary information about the study protocol, including: disease or condition; intervention (e.g., the medical product, behavior, or procedure being studied); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for providing patient health information) and PubMed (for providing citations and abstracts of academic articles in the medical field). Idelalisib is listed in the database. Zydelig in combination with rituximab is used to treat patients with relapsed chronic lymphocytic leukemia (CLL) for whom rituximab monotherapy is more appropriate due to comorbidities. /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 for this indication was based on overall response rate (ORR) data. This indication has not been shown to improve patient survival or disease-related symptoms. Continued approval for this indication may depend on validation 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
/Black Box Warning/ Warning: Fatal and Serious Toxicity: Hepatotoxicity. Fatal and/or serious hepatotoxicity occurs in 16% to 18% of patients treated with Zydelig. Liver function should be monitored before and during treatment. Discontinue Zydelig treatment as advised, then reduce the dose or discontinue the medication.
/Black Box Warning/ Warning: Fatal and Serious Toxicity: Severe Diarrhea, Colitis. Fatal and/or severe diarrhea or colitis occurs in 14% to 20% of patients treated with Zydelig. Monitor for severe diarrhea or colitis. Discontinue and reduce or stop Zydelig as advised.
/Black Box Warning/ Warning: Fatal and Serious Toxicity: Pneumonia. Fatal and/or severe pneumonia occurs in 4% of patients treated with Zydelig. Monitor for pulmonary symptoms and bilateral interstitial infiltration. Discontinue or stop Zydelig as advised.
/Black Box Warning/ Warning: Fatal and Serious Toxicity: Infection. Fatal and/or severe infection occurs in 21% to 48% of patients treated with Zydelig. Monitor for signs and symptoms of infection. Discontinue Zydelig if infection is suspected.
For more complete data on Idelalisib drug warnings (of 20), please visit the HSDB record page.

---

1. Mechanism of action: Idelalisib selectively inhibits PI3Kδ, a key kinase in the B cell receptor (BCR) signaling pathway. It blocks PI3Kδ-mediated AKT activation, inhibits B cell proliferation/survival and cytokine-induced inflammation, thereby targeting B cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma) and neuroinflammation (stroke). ^[1]>
[2][3][4]
2. Preclinical significance: - Literature [1]/[2]: confirmed that Idelalisib is a candidate drug for B cell malignancies, showing efficacy in primary CLL cells and transgenic models.
[1][2]
- Literature [3]: identified PI3Kδ as a target of neuroinflammation; Idelalisib can reduce stroke infarct volume and neurological deficits.
[3]
- Literature [4]: It was confirmed that it has a synergistic effect with PI3Kδ regulatory subunit inhibitors, which can overcome rituximab resistance in diffuse large B-cell lymphoma (DLBCL).
[4]
3. Clinical significance: It was subsequently approved for the treatment of relapsed chronic lymphocytic leukemia (CLL), follicular lymphoma and small lymphocytic lymphoma (not reported in the literature, but supported by preclinical data) ^[1]
[2]

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

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.02 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (6.02 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

View More

Solubility in Formulation 3: ≥ 2.5 mg/mL (6.02 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

Solubility in Formulation 4: 30%PEG 400 (dissolve first)+0.5% Tween 80 +5% Propylene glycol : 30mg/mL

---

 (Please use freshly prepared in vivo formulations for optimal results.)