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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.

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.

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.

/SIGNS AND SYMPTOMS/ Idelalisib may cause fetal harm if administered to pregnant women; teratogenicity and embryofetal toxicity have been demonstrated in animals receiving idelalisib at dosages equivalent to 12-30 times the human exposure at the recommended dosage. Pregnancy should be avoided during therapy and for at least 1 month after drug discontinuance.

/SIGNS AND SYMPTOMS/ Severe (grade 3 or 4) neutropenia has been reported in 31% of patients receiving idelalisib in clinical studies. .

/SIGNS AND SYMPTOMS/ Fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have occurred in patients treated with Zydelig. If SJS or TEN is suspected, interrupt Zydelig until the etiology of the reaction has been determined. If SJS or TEN is confirmed, permanently discontinue Zydelig. Other severe or life-threatening (Grade =3) cutaneous reactions, including dermatitis exfoliative, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, exfoliative rash, and skin disorder, have been reported in Zydelig-treated patients.

/SIGNS AND SYMPTOMS/ 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.

For more Human Toxicity Excerpts (Complete) data for Idelalisib (12 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Idelalisib

vMost-DILI-concern

8

Box warning

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ 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 at exposures 0.40/0.62-fold (male/female), compared to the exposure in patients with hematologic malignancies administered the recommended dose of 150 mg twice daily.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 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 = 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). The dose of 75 and 150 mg/kg/day of idelalisib in rats resulted in exposures (AUC) of approximately 12 and 30 times, respectively, the human exposure at the recommended dose of 150 mg twice daily.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 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. The high dose in females resulted in an exposure (AUC) that is approximately 17-fold the exposure in patients at the recommended dose of 150 mg twice daily.

/GENOTOXICITY/ 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.

/ALTERNATIVE and IN VITRO TESTS/ Idelalisib (an inhibitor of phosphatidylinositol-3-kinase-delta) is approved for treatment of B-cell malignancies, with a Boxed Warning concerning potentially fatal hepatic, lung, and intestinal toxicities. The mechanisms of these tissue-specific adverse events have yet to be elucidated. This in vitro study investigated whether these effects could be attributed, at least in part, to altered cellular bioenergetics. A phosphorescence analyzer was used to measure cellular mitochondrial O2 consumption (kc, uM O2/min/mg) in C57BL/6 mouse organs in the presence of 10 uM idelalisib or dimethyl-sulfoxide. Idelalisib significantly reduced the rate of cellular respiration in liver and lung fragments by 20% and 27%, respectively. Respiration in intestinal, thymic, and kidney fragments was unaffected. Idelalisib did not alter respiratory chain activities in mitochondria isolated from the liver and did not induce hepatocyte death. Thus, the drug mildly lowers liver and lung cellular respiration, an effect that may contribute to toxicities observed in these organs.

Idelalisib may cause fetal harm if administered to pregnant women; teratogenicity and embryofetal toxicity have been demonstrated in animals receiving idelalisib at dosages equivalent to 12-30 times the human exposure at the recommended dosage. Pregnancy should be avoided during therapy and for at least 1 month after drug discontinuance.

Idelalisib is contraindicated in patients with a history of serious hypersensitivity reactions, including anaphylaxis and toxic epidermal necrolysis.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including idelalisib, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Antineoplastic Agents; Enzyme Inhibitors

MEDICATION