Has an asymmetric carbon atom and can exist as the optically active forms S(-) and R(+), and is produced as a reacemic mixture with a net optical rotation of zero
Lenalidomide is not subject to extensive hepatic metabolism involving CYP enzymes and metabolism contributes to a very minor extent to the clearance of lenalidomide in humans. Lenalidomide undergoes hydrolysis in human plasma to form 5-hydroxy-lenalidomide and N-acetyl-lenalidomide. Unchanged lenalidomide is the predominant circulating drug form, with metabolites accounting for less than five percent of the parent drug levels in the circulation.
Lenalidomide -undergoes limited metabolism. Unchanged lenalidomide is the predominant circulating component in humans. Two identified metabolites are hydroxy-lenalidomide and N-acetyl-lenalidomide; each constitutes less than 5% of parent levels in circulation.
IDENTIFICATION AND USE: Lenalidomide is off-white to pale-yellow solid powder. Lenalidomide, a thalidomide analog, is an immunomodulatory agent with antineoplastic and antiangiogenic activity. Lenalidomide is used for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. It is also used for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. It is used in combination with dexamethasone for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. HUMAN EXPOSURE AND TOXICITY: Lenalidomide can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide's structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant. Lenalidomide has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma who were treated with lenalidomide and dexamethasone therapy. Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. Patients with multiple myeloma treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Lenalidomide can cause significant neutropenia and thrombocytopenia. Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Angioedema and serious dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in lenalidomide-treated patients. These reactions can be fatal. ANIMAL STUDIES: Acute administration of lenalidomide to rats and mice via intravenous and oral administration did not result in mortality. However, repeated oral administration of 4 and 6 mg/kg/day to monkeys for up to 20 weeks produced mortality and significant toxicity. The embryotoxic and teratogenic potential of lenalidomide was studied in rats, rabbits and monkeys. A pre- and post-natal development study in rats revealed few adverse effects in the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg. In rabbits, no limb abnormalities were attributable to lenalidomide in the offspring of females administered 3, 10 and 20 mg/kg/day orally. Developmental toxicity at the 10 and 20 mg/kg/day dose levels was characterized by slightly reduced fetal body weights, increased incidences of post implantation loss (early and late resorptions and intrauterine deaths), and gross external findings in the fetuses associated with morbidity and pharmacotoxic effects of lenalidomide (purple discoloration of the skin on the entire body). An absence of the intermediate lobe of the lung was observed at 10 and 20 mg/kg/day with dose dependence and displaced kidneys were observed at 20 mg/kg/day. Soft tissue and skeletal variations in the fetuses were also observed at 10 and 20 mg/kg/day. These included minor variations in skull ossification (irregular nasal-frontal suture) and small delays in ossification of the metacarpals, associated with the reduced fetal body weights. In monkeys, malformations were observed in the offspring of female monkeys who received lenalidomide doses as low as 0.5 mg/kg/day during pregnancy. The observed malformations ranged from stiff and slightly malrotated hindlimbs at 0.5 mg/kg/day of lenalidomide up to severe external malformations, such as bent, shortened, malformed, malrotated, and/or absent part of the extremities, oligo- or polydactyly at 4 mg/kg/day of lenalidomide. Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats.
Serum enzyme elevations occur in 8% to 15% of patients taking lenalidomide and are more frequent with higher doses. The enzyme abnormalities are usually mild and self-limited, and only rarely require drug discontinuation. In addition, lenalidomide has been implicated in rare instances of clinically apparent, acute liver injury which can be severe and has led to deaths from acute liver failure. The onset of injury is typically within 1 to 8 weeks of starting therapy. The pattern of serum enzyme elevation at the time of presentation can be either hepatocellular or cholestatic; however, the injury tends to be cholestatic and can be prolonged. Immunoallergic and autoimmune features are not common. Several instances of acute liver injury associated with lenalidomide therapy have occurred in patients with other apparent causes of liver disease or with preexisting chronic hepatitis B or C. If performed during the acute injury, liver biopsy shows hepatocellular necrosis and inflammatory cell infiltration, consistent with acute drug induced injury. In some instances there is bile duct injury and loss resulting in progressive cholestatic liver injury suggestive of vanishing bile duct syndrome. Lenalidomide has also been shown to increase indirect bilirubin levels in patients with underlying Gilbert syndrome, causing a mild hyperbilirubinemia during therapy that soon resolves with stopping treatment and is otherwise benign.
Thalidomide and its derivatives have also been implicated in causing an increased risk of graft-vs-host disease after autologous or allogeneic hematopoietic stem cell transplantation (HSCT) as well as after liver, kidney and heart transplantation. There appears to be cross reactivity to this complication among lenalidomide, pomalidomide and thalidomide. Therapy usually requires discontinuation of the antineoplastic agent as well as treatment with high doses of corticosteroids and tacrolimus or sirolimus. Furthermore, hepatic graft-vs-host disease can occasionally present with an acute hepatitis that resembles hepatocellular drug induced liver injury.
Reactivation of hepatitis B has been reported in patients receiving thalidomide, lenalidomide and pomalidomide, but generally only after HSCT and the role of these agents in causing reactivation is not always clear. Indeed, in studies of large numbers of patients treated for multiple myeloma, the major risk factor for reactivation was found to be HSCT rather than the specific antineoplastic drugs being used. Indeed, lenalidomide therapy is associated with a reduced risk of reactivation in patients with HSCT (although dexamethasone, thalidomide and bortezomib were not), perhaps because of the immune enhancement typically caused by lenalidomide.
Likelihood score: C (probable rare cause of clinically apparent liver injury).
口服给药后，来那度胺迅速吸收，具有很高的生物利用度。其达峰时间（Tmax）为0.5至6小时。来那度胺表现出线性药代动力学特征，其曲线下面积（AUC）和峰浓度（Cmax）随剂量成比例增加。多次给药不会导致药物累积。在健康男性受试者中，峰浓度（Cmax）为413 ± 77 ng/ml，无限面积（AUCinfinity）为1319 ± 162 h x ng/ml。
Following oral administration, lenalidomide is rapidly absorbed with high bioavailability. It has a Tmax ranging from 0.5 to six hours. Lenalidomide exhibits a linear pharmacokinetic profile, with its AUC and Cmax increasing proportionally with dose. Multiple dosing does not result in drug accumulation. In healthy male subjects, the Cmax was 413 ± 77 ng/ml and the AUCinfinity was 1319 ± 162 h x ng/ml.
Lenalidomide is eliminated predominantly via urinary excretion in the unchanged form. Following oral administration of 25 mg of radiolabeled lenalidomide in healthy subjects, about 90% of the dose (4.59% as metabolites) was eliminated in urine and 4% of the dose (1.83% as metabolites) was eliminated in feces within ten days post-dose. Approximately 85% of the dose was excreted as lenalidomide in the urine within 24 hours.
来源:DrugBank
吸收、分配和排泄
分布容积
在健康的男性受试者中，表观分布容积为75.8 ± 7.3升。
In healthy male subjects, the apparent volume of distribution was 75.8 ± 7.3 L.
[EN] METHODS FOR SYNTHESIZING 3-(SUBSTITUTED DIHYDROISOINDOLINONE-2-YL)-2,6-DIOXOPIPERIDINE, AND INTERMEDIATES THEREOF [FR] PROCÉDÉS POUR LA SYNTHÈSE DE 3-[(DIHYDROISOINDOLINONE SUBSTITUÉE)-2-YL]-2,6-DIOXOPIPÉRIDINE ET INTERMÉDIAIRES CORRESPONDANTS
of traditional small-molecule drugs. Based on PROTACs approaches, several BRD4 degraders were developed and have been proved to degrade BRD4 protein and inhibit tumor growth. Herein, we present the design, synthesis, and biological evaluation of pyrrolopyridone derivative-based BRD4 degraders. Four synthesized compounds displayed comparative potence against BRD4 BD1 with IC50 at low nanomolar concentrations
target BRD4 recently. Herein, we present our design, synthesis and biologicalevaluation of a new class of PROTAC BRD4 degraders, which were based on a potent dihydroquinazolinone-based BRD4 inhibitor compound 6 and lenalidomide/pomalidomide as ligand for E3 ligase cereblon. Gratifyingly, several compounds showed excellent inhibitory activity against BRD4, and high anti-proliferative potency against human
