Daurismo

Uses

Daurismo is a sonic hedgehog receptor inhibitor used to treat newly diagnosed acute myeloid leukemia in patients over 75 years who cannot receive intense chemotherapy.

Daurismo, 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.

Daurismo is also used to associated treatment for these conditions: Acute Myeloid Leukemia (AML)

How Daurismo works

Daurismo 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.

Toxicity

Daurismo 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.

Food Interaction

• Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of glasdegib.
• Take at the same time every day.
• Take with or without food.

[Moderate] GENERALLY AVOID: Coadministration with grapefruit or grapefruit juice may increase the plasma concentrations of glasdegib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit.

When glasdegib was coadministered with ketoconazole, a potent CYP450 3A4 inhibitor, glasdegib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.4- and 2.4-fold, respectively, compared to administration of glasdegib alone.

The interaction has not been studied with other, less potent CYP450 3A4 inhibitors.

Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability).

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

When administered with a high-fat, high-calorie meal (800 to 1000 total calories, 500 to 600 fat calories, 250 carbohydrate calories, and 150 protein calories), glasdegib Cmax and AUC decreased by 31% and 16%, respectively.

MANAGEMENT: Daurismo may be administered with or without food.

Coadministration of grapefruit or grapefruit juice with glasdegib should preferably be avoided.

Daurismo Disease Interaction

Moderate: QT interval prolongation, renal/hepatic

Volume of Distribution

Daurismo reported volume of distribution in a dose of 50 mg is of 225 L.

Elimination Route

Daurismo 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.

Half Life

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

Clearance

The clearance rate of 50 mg of glasdegib is reported to be of 5.22 L/h.

Elimination Route

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.

Innovators Monograph

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