ziftomenib

Action and Spectrum

Action and spectrum:    

Actions:  

Ziftomenib is a menin inhibitor that disrupts the interaction between menin and lysine-specific methyltransferase 2A (KMT2A). In acute leukemias, NPM1 mutations can drive disease progression by drawing the normal menin–KMT2A complex to promoters of genes that promote leukemogenesis. The NPM1 mutations that respond to this therapy are those that eliminate the nucleolar localization signal and introduce a new nuclear export signal, causing the mutant NPM1 protein to accumulate in the cytoplasm. This mislocalization interferes with normal cellular processes and contributes to leukemia development by altering gene expression patterns. 

Drug Interaction

Adverse Reaction

Frequency Defined    

>10% 

QTc prolongation, Grades 1-3 (12%) 

All grades 

Febrile neutropenia (22%)
Pruritus (23%)
Differentiation syndrome (26%)
Potassium increased (26%)
Bilirubin increased (27%)
Bacterial infection (28%)
Edema (30%)
Fatigue (34%)
Nausea (35%)
Diarrhea (36%)
Hemorrhage (38%)
Alk Phos increased (41%)
Creatinine increased (45%)
Sodium decreased (49%)
ALT increased (50%)
Albumin decreased (51%)
Infection without identified pathogen (52%)
Potassium decreased (52%)
AST increased (53%) 

Grades 3-4 

Differentiation syndrome (13%)
Bacterial infection (17%)
Potassium decreased (22%)
Leukocytosis (22%)
Infection without identified pathogen (38%) 

1-10% 

QTc prolongation, Grades 3 (8%) 

All Grades 

Hypoxia (9%) 

Grades 3-4 

Diarrhea (5%)
Hypertension (5%)
Viral infection (5%)
Hypoxia (5%)
Potassium increased (6%)
Bilirubin increased (6%)
ALT increased (6%)
Renal impairment (6%)
Electrocardiogram QT prolonged (8%)
Transaminases increased (8%)
Fatigue (8%)
Hemorrhage (8%)

Black Box Warning

Black Box Warning   

Differentiation syndrome    

Contraindication / Caution

Contraindication/Caution:    

Contraindication  

None 

Pregnancy / Lactation

Pregnancy Warnings:    

Pregnancy category: N/A    

Lactation: Excretion in human breastmilk is unknown    

Pregnancy categories:    

Category A: Satisfactory and well-controlled studies show no evidence of risk to the fetus in the first trimester or in the later trimester.    

Category B: No evidence of risk to fetus found in animal reproduction studies and there are not enough studies on pregnant women.    

Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for an effect in humans, care must be taken for potential risks in pregnant women.    

Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite potential risks may be used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category clearly outweigh risks over benefits. These category drugs should be prohibited for pregnant women.     

Category N: There is no data available for the drug under this category.     

Pharmacology

Pharmacology:    

Ziftomenib is a menin inhibitor that disrupts the interaction between menin and lysine-specific methyltransferase 2A (KMT2A). In acute leukemias, NPM1 mutations can drive disease progression by drawing the normal menin–KMT2A complex to promoters of genes that promote leukemogenesis. The NPM1 mutations that respond to this therapy are those that eliminate the nucleolar localization signal and introduce a new nuclear export signal, causing the mutant NPM1 protein to accumulate in the cytoplasm. This mislocalization interferes with normal cellular processes and contributes to leukemia development by altering gene expression patterns. 

Pharmacokinetics:    

Absorption 

The drug reaches its peak plasma concentration at about 4.1 hours after administration and has an absolute bioavailability of approximately 12.9 percent. 

Distribution 

The drug is highly protein bound, with about 99% bound to albumin, and it has a very large volume of distribution of roughly 30,100 liters. 

Metabolism 

It is metabolized mainly by the CYP3A enzyme system. 

Excretion and Elimination 

The drug has a half-life of about 189.8 hours when taken with strong CYP3A4 inhibitors and approximately 93.6 hours when taken without them. Its clearance is 41.5 L/hr in the presence of strong CYP3A4 inhibitors and 101.2 L/hr when those inhibitors are not used. Most of the drug is eliminated through the feces, with around 86% recovered (73% as unchanged drug), while only about 0.5% is excreted in the urine, including 0.03% unchanged. 

Adminstartion

Administration:    

For oral use, the drug should be taken on an empty stomach, either at least one hour before eating or two hours after a meal. It should be taken at roughly the same time every day. The capsules must be swallowed whole and should not be opened, broken, or chewed. 

Patient Information Leaflet

Patient information leaflet    

Generic Name: ziftomenib 

Why do we use ziftomenib ?   

Ziftomenib is used for the treatment of adults with relapsed or refractory acute myeloid leukemia (AML) whose disease harbors an NPM1 mutation. It is specifically intended for patients who have already undergone prior therapy but whose leukemia has either returned or not responded adequately to treatment. Ziftomenib targets the underlying molecular abnormality associated with NPM1-mutated AML, offering a therapeutic option for a subset of patients with limited alternatives.