Ponatinib

Ponatinib is a tyrosine kinase inhibitor that inhibits tumor cell proliferation by targeting the activity of BCR-ABL fusion protein (including T315I mutant) and various other kinases (such as VEGFR, PDGFR, FGFR, etc.), blocking abnormal signal transduction.

1. Indications

Ponatinib is a kinase inhibitor suitable for the treatment of the following adult patients:

1. Chronic myeloid leukemia (CML) in chronic phase, accelerated phase or blast phase, and is resistant or intolerant to previous tyrosine kinase inhibitor (TKI) treatment

2. Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), and is resistant to previous treatment with tyrosine kinase inhibitors (TKI) Resistance or intolerance to tyrosine kinase inhibitor (TKI) treatment

II. Mechanism of action

Ponatinib is a multi-target tyrosine kinase inhibitor that mainly exerts anti-tumor effects through the following mechanisms:

1. Inhibits the tyrosine kinase activity of BCR-ABL and its T315I mutant (IC50 is 0.4 and 2.0 nM respectively)

2. Inhibition VEGFR, PDGFR, FGFR, EPH receptors and SRC family kinases

3. Block the activity of kinases such as KIT, RET, TIE2 and FLT3

4. Shown in animal models to reduce the size of tumors expressing native or T315I mutant BCR-ABL

3. Usage and dosage

1. Recommended Dosage

Standard dose : 45 mg orally, once a day (can be taken with food or on an empty stomach)

Dosing method : Swallow the tablet whole, do not chew, crush or break it

Continue treatment until disease progression or unacceptable toxicity occurs

Myelosuppression-related adjustments:

First First occurrence of ANC <1×10⁹/L or platelet <50×10⁹/L: suspend administration, resume with 45 mg

Second occurrence: resume with 30 mg after suspension

Third occurrence: resume with 15 mg after suspension

Non-hematological toxicity adjustment:

Hepatotoxicity:

ALT/AST>3×ULN: Resume at 30 mg after pause

Reoccurrence: Resume at 15 mg after pause

ALT/AST>3×ULN and bilirubin >2×ULN: Permanent discontinuation

Pancreatitis:

Asymptomatic grade 3-4 lipase elevation: Resume at 30 mg after pause

Symptomatic grade 3 pancreatitis: Resume at 30 mg after pause

Grade 4 pancreatitis: permanent discontinuation

Combined use with strong CYP3A inhibitors:

Dose should be reduced to 30 mg once daily

IV. Common adverse reactions Reactions (≥20%):

1. Systemic : Fatigue (39%), fever (23%)

2. Cardiovascular : < /b>Hypertension (68%)

3. Skin : Rash (54%), dry skin (39%)

4. Gastrointestinal c:Abdominal pain (49%), constipation (37%), nausea (23%)

5. Musculoskeletal :Arthralgia (26%), myalgia (22%)< /p>

6. Nervous system : Headache (39%), peripheral neuropathy (13%)

Serious adverse reactions:

1. Blood system : thrombocytopenia (36%), neutropenia (24%), anemia (9%)

2. Cardiovascular : cardiac Failure (4%), arrhythmia (5%)

3. Digestive system :Pancreatitis (6%), GI bleeding (4%)

4. Other u 200c:Fluid retention (3%), tumor lysis syndrome (<1%)

Key precautions:

1. Arterial thrombosis : In clinical trials, 8% of patients developed severe arterial thrombosis (including fatal myocardial infarction and stroke)

2. Hepatotoxicity : may cause liver failure or even death

5. Medication precautions Important monitoring requirements:

1. Cardiovascular : Regular ECG monitoring before and during treatment

2. Hematology u 200c: Complete blood count before treatment and every 2 weeks for the first 3 months, and once a month thereafter

3. Liver function : Baseline and periodic testing of ALT/AST/bilirubin

4. Pancreas : Serum lipase test every 2 weeks for the first 2 months

Drug interactions:

Strong CYP3A inhibitor : the dose needs to be reduced to 30 mg/day (such as ketoconazole)

Strong CYP3A inducer : avoid combined use (such as rifampicin)

Gastric pH-raising drug : may reduce ponatinib bioavailability (such as PPI)