N-[(2R,4R)-2-(1H-Benzimidazol-2-yl)-1-methyl-4-piperidinyl]-N′-(4-cyanophenyl)urea

374.43898

374.44

K673DMO5H9

C84862

L01XX63|L - Antineoplastic and immunomodulating agents

96.8

2.4

1.3±0.1 g/cm3

> 214 ºC

Decomposes at 214 ºC

336.9±31.5 °C

1.686

0.02

6

Ⅲ

2811

6.1

P201, P202, P260, P281, P308+P313, P314, P405, P501

H361

|Warning|H361 (100%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]|P201, P202, P260, P281, P308+P313, P314, P405, and P501|Aggregated GHS information provided by 3 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Glasdegib is not mutagenic in bacterial reverse mutation assays and is not clastogenic in _in vitro_ chromosome aberration assays. In fertility studies, glasdegib has the potential to impair reproductive function in males due to the production of testicular changes such as hypospermatogenesis. Overdose by glasdegib starts at 640 mg/day and shows to present nausea, vomiting, dehydration, fatigue, and dizziness. In case of overdose, symptomatic treatment and ECG monitoring are advised. The reported oral LD50 in rat of gladegib administered in triacetin is reported to be of 3000 mg/kg.

Elevations in serum ALT levels are common during glasdegib therapy, occurring in 31% of patients and rising above 5 times the upper limit of the normal range in 11%. Glasdegib has had limited clinical use but has not been linked to instances of acute liver injury with symptoms or jaundice. Because of the limited clinical experience with the use of hedgehog inhibitors, their potential for causing liver injury is not well defined.

Glasdegib is reported to be 91% protein bounded which is explained due to its high lipophilic profile.

Glasdegib, in combination with cytarabine, is indicated for the treatment of newly diagnosed acute myeloid leukemia in adult patients who are over 75 years old or that have co-morbidities that preclude intensive induction chemotherapy. Acute myeloid leukemia is characterized by abnormal production of myeloblasts, red cells, or platelets. It is considered a cancer of blood and bone marrow and it is the most common type of acute leukemia in adults.|FDA Label|Treatment of acute myeloid leukaemia|Daurismo is indicated, in combination with low-dose cytarabine, for the treatment of newly diagnosed de novo or secondary acute myeloid leukaemia (AML) in adult patients who are not candidates for standard induction chemotherapy.

Glasdegib is an orally available small molecule inhibitor of the signaling molecule hedgehog which is used as an antineoplastic agent in the treatment of acute myeloid leukemia. Glasdegib is associated with a moderate rate of serum aminotransferase elevations during therapy and is suspected to cause rare instances of clinically apparent acute liver injury.

Antineoplastic Agents

In preclinical studies, glasdegib achieved a significant reduction in leukemic stem cell burden in xenograft models and a reduction in cell population expressing leukemic stem cell markers. In clinical trials, glasdegib demonstrated a marked downregulation of more than 80% of the expression of glioma-associated transcriptional regulator GL11 in skin. In this same study 8% of the studied individuals with acute myeloid leukemia achieved morphological complete remission while 31% achieved stable disease state. The latest clinical trial proved glasdegib to generate an overall survival of 8.3 months which was almost double to what has been observed in patients under low-dose cytarabine treatment. As well, there have been reports of dose-dependent QTc prolongation in patients administered with glasdegib.

Glasdegib presents a dose-proportional pharmacokinetic profile which is observed by the presence of a broad dose-proportional maximum plasma concentration. In this study and on a dose of 50 mg, the median time to reach a maximum concentration of 321 ng/ml was of 4 hours with an AUC of 9587 ng.h/ml. The oral bioavailability of glasdegib is reported to be of 55%. In a multiple dose study of 50 mg, the Cmax, tmax and AUC was reported to be 542 ng/ml, 4 h and 9310 ng.h/ml respectively. In this same study, the average concentration at a steady state was of 388 ng/ml. The absorption rates of glasdegib can be modified by the concomitant consumption of a high-fat, high-calorie meal.|From the administered dose of glasdegib, 49% is eliminated in the urine from which 17% is excreted as the unchanged form while 42% is eliminated in feces where 20% represents the unchanged form.|Glasdegib reported volume of distribution in a dose of 50 mg is of 225 L.|The clearance rate of 50 mg of glasdegib is reported to be of 5.22 L/h.

After oral administration, glasdegib was primarily metabolized by CYP3A4 with minor contributions of CYP2C8 and UGT1A9. The amount of unchanged glasdegib in plasma accounts only for 69% of the administered dose.

The reported half-life of glasdegib is of 17.4 hours.

Glasdegib is a potent and selective inhibitor of the hedgehog signaling pathway that acts by binding to the smoothened (SMO) receptor. The hedgehog signaling pathway is involved in maintenance of neural and skin stem cells. In this pathway, the binding of specific ligands to the transmembrane receptor patched (PTCH1) allows the activation of the transcriptional regulators GL11, GL12 and modulation of the gene expression through SMO-mediated signaling. The aberrant activation of the hedgehog pathway is thought to be implicated in the pathogenesis of chronic myeloid leukemia, medulloblastoma and basal cell carcinoma due to the hyperproliferative state that a modification on this pathway will produce.

1-(2-(1H-benzo(d)imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea

Human drugs -> Rare disease (orphan)|Human Drugs -> EU pediatric investigation plans|Human drugs -> Orphan -> Daurismo -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients