Ponatinib – Mechanism of Action, Indications, Usage, Side Effects



All  first- and second-generation inhibitors are ineffective against the BCR-ABL T315I ‘‘gatekeeper’’ mutation. In order to overcome this issue and to further improve the inhibitory effect, the third generation inhibitor ponatinib was developed. 

Related PostRuxolitinib – Indication, Usage, and Side Effects.


The exchange of threonine at position 315 for the more bulky isoleucine leads to a steric hindrance, inhibiting binding of all these inhibitors. Unable to bind the kinase, most Abl inhibitors lose their ability to block the BCR-ABL function. Twenty percent of patients who are imatinib resistant because of a BCR-ABL mutation bear the T315I ‘‘gatekeeper’’ mutation.

The small molecule ponatinib was developed specifically to overcome resistance based on the T315I mutation. The integration of a linear carbon–carbon triple bond into the structure of the molecule to link two functional groups avoids the blocking effect of the isoleucine in the context of the T315I mutation


Peak concentrations of ponatinib are observed within 6 hours after oral administration. Drugs that elevate the gastric pH may reduce ponatinib bioavailability. CYP3A4 involved in the phase I metabolism of ponatinib. Ponatinib is also metabolized by esterases and/or amidases. Ponatinib is mainly eliminated via feces.


Adult  patients with chronic myeloid leukemia (CML) resistant or intolerant to prior tyrosine kinase inhibitor therapy

    • chronic phase,
    • accelerated phase, or
    • blast phase


  • 45 mg administered orally once daily with or without food.
  • Tablets should be swallowed whole.
  • 15 mg and 45 mg round, white, film-coated tablets.


  • Myelosuppression
    • ANC <1.0 x 10^9/L or platelets <50 x 10^9/L
    • First occurrence: Hold ponatinib until ANC ≥1.5 x 10^9/L and platelets ≥75 x 10^9/L and resume at initial dose of 45 mg.
    • Second occurrence: Hold ponatinib until ANC ≥1.5 x 10^9/L and platelets ≥75 x 10^9/L and resume at 30 mg after recovery.
    • Third occurrence: Hold ponatinib until ANC ≥1.5 x 10^9/L and platelets ≥75 x 10^9/L and resume at 15 mg after recovery.
  • Serum lipase elevation

    • Grade 1 or 2 (asymptomatic): Consider dose interruption or reduction.
    • Grade 3 or 4 (>2 x IULN) (asymptomatic) or asymptomatic radiologic pancreatitis: 
      • Hold drug until serum levels are <1.5 x ULN. Resume at lower dose after recovery (30 mg if patient receiving 45 mg; 15 mg if patient receiving 30 mg.Discontinue ponatinib if patient receiving 15 mg).
  • Pancreatitis (symptomatic),
    • Grade 3:
      • Hold drug until serum lipase levels are ≤grade 1.
      •  Resume at lower dose after recovery (30 mg if patient receiving 45 mg; 15 mg if patient receiving 30 mg). Discontinue ponatinib if patient receiving 15 mg.
    •  Grade 4: Discontinue ponatinib.
  • Liver transaminase

    •  >3 x ULN (grade ≥2):
      •  Hold drug until serum levels are <3 x IULN. Monitor hepatic function. Resume at lower dose after recovery
    • AST or ALT ≥3 x ULN concurrent with bilirubin >2 x ULN and alkaline phosphatase <2 x ULN:
      • Discontinue ponatinib
  • Geriatric Use
  • Patients of age ≥ 65 years may be
    more likely to experience adverse reactions including decreased platelet count, peripheral edema, increased lipase, dyspnea,
    asthenia, muscle spasms, and decreased appetite. 

In general, dose selection for an elderly patient should be cautious.


    • The most common non-hematologic adverse reactions (≥ 20%) were
      hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation,
      arthralgia, nausea, and pyrexia.
    • Hematologic adverse reactions included
      thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia
    • Thrombosis and Thromboembolism :: Arterial thrombosis
      • Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in 8%
      • Myocardial infarction or worsening coronary artery disease 
        • most common arterial thrombosis event and occurred in 5% of patients.
        •  50% of these patients developed congestive heart failure concurrent or subsequent to the myocardial ischemic event.
      • Serious cerebrovascular events were reported in 2% (8/449). 
        • hemorrhagic conversion of the initial ischemic event. 
        • stenosis of large arterial vessels of the brain (e.g., carotid, vertebral, middle cerebral artery).
      • Serious peripheral arterial events were reported in 2% . (digital
        or distal extremity necrosis, peripheral arterial disease and required
      • Myocardial  infarction, coronary artery disease, angina, stroke, transient ischemic attack, hypertension, diabetes mellitus, hyperlipidemia, and smoking are associated with increased risk of arterail thrombosis.
    • Venous thromboembolic : events occurred in 3% patients
      • deep venous thrombosis 
      • pulmonary embolism 
      • portal vein thrombosis
      • retinal vein thrombosis
    • Congestive Heart Failure (4%)
    • Pancreatitis
      • occurred in 6% of patients 
      • pancreatitis resolved within 2 weeks with dose interruption or reduction.
      • incidence of treatment-emergent lipase elevation is 41%.
      • In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment.
    • Hemorrhage
      • Serious bleeding events, occurred in 5%.
      • Bleeding events is higher in patients with AP-CML, BP-CML, and Ph+ALL. 
      • Cerebral hemorrhage and gastrointestinal hemorrhage were the most commonly reported serious bleeding events.
      • Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia
    • Fluid Retention
      • Fluid  retention occurred in 23% of the patients. 
      • most common fluid retention events were peripheral edema
        pleural effusion  and pericardial effusion .
    • Cardiac Arrhythmias
    • Myelosuppression
  • Tumor Lysis Syndrome


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