Review of Selected New Molecular Entities
Review of Selected New Molecular Entities
Ponatinib is a new multitargeted tyrosine kinase inhibitor (TKI) approved as an orphan drug under the FDA's accelerated approval program. It is indicated to treat patients with chronic-, accelerated-, or blast-phase chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior TKI therapy. CML and Ph+ALL are WBC cancers that affect more than 20,000 people in the United States. They are typically asymptomatic initially, but an enlarged spleen, fatigue, paleness from anemia, and disrupted thermoregulation may develop. Ponatinib is the third drug approved for CML treatment since 2012; the others are bosutinib (Bosulif) and omacetaxine (Synribo).
Approval of ponatinib was based on a single-arm, open-label, multicenter, phase II trial involving >449 patients with CML or Ph+ALL whose disease was resistant or intolerant to prior TKI therapy. Ponatinib 45 mg once daily resulted in a reduction in the percentage of cells expressing the Philadelphia chromosome genetic mutation (major cytogenetic response) in 54% of patients, including 70% of patients who also had a T315I mutation. Ponatinib also resulted in a normalization of WBC counts or no evidence of leukemia (major hematologic response) in 52% of accelerated-phase CML patients, 31% of blast-phase CML patients, and 41% of Ph+ALL patients.
Ponatinib is an imidazo[1,2-b]pyridazine benzamide (Figure 1) that functions as a TKI. Its primary target is the breakpoint cluster region–Abelson (Bcr-Abl) tyrosine kinase expressed by CML and Ph+ALL, but it also targets Bcr-Abl isoforms that carry mutations, including the T315I mutation. Ponatinib also binds to members of the VEGFR, PDGFR, FGFR, and EPH receptors and SRC families of kinases, and to KIT, RET, TIE2, and FLT3.
(Enlarge Image)
Figure 1.
Ponatinib
The absolute bioavailability of ponatinib is unknown. The drug has a half-life of 24 hours, and it is >99% plasma protein bound. Ponatinib is metabolized by CYP3A4 and, to a lesser extent, by CYP2C8, 2D6, 3A5, and esterases and amidases. Approximately 64% of ponatinib is excreted as metabolites, primarily in the feces. Ponatinib does not inhibit metabolism of other CYP-substrate drugs, nor does it appear to induce CYP metabolism. It does, however, inhibit adenosine triphosphate–binding cassette (ABC) G2, the bile salt export pump, and the P-glycoprotein (Pgp) pump.
The most common ARs (≥20%) reported in clinical trials were myelosuppression (thrombocytopenia, neutropenia, leukopenia, anemia, and lymphopenia), hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Ponatinib also carries a Black Box Warning that the drug may cause arterial thrombosis and hepatotoxicity. The drug should be avoided in pregnancy because of its potential for fetal harm (Pregnancy Category D). Patients who breastfeed or intend to breastfeed should not use ponatinib.
The ponatinib dosage should be reduced when the drug is coadministered with CYP3A inhibitors. Coadministration of ponatinib with strong CYP3A inducers or drugs that elevate gastric pH (proton pump inhibitors, H2 blockers, antacids) may lead to inadequate drug concentration. Because of its inhibition of Pgp and ABC, ponatinib may result in altered efficacy of drugs that are sensitive substrates of these pumps; however, formal studies have not been conducted to determine the severity of this interaction.
Ponatinib is supplied as 15-mg and 45-mg tablets. The recommended dosage is 45 mg once daily with or without food. The dosage should be reduced to 30 mg once daily when the drug is administered with strong CYP3A inhibitors. Ponatinib has not been studied in pediatric patients or in hepatically or renally impaired patients. Ponatinib therapy should be interrupted for 1 week prior to major surgery to avoid an increased bleeding risk. Patients taking ponatinib who experience myelosuppression, hepatic toxicity, asymptomatic lipase elevation (grade 3–4), or pancreatitis (grade 2–3) should interrupt therapy until toxicity subsides, then resume therapy at the dosage recommended by the manufacturer.
Ponatinib (Iclusig, Ariad Pharmaceuticals)
Indication and Clinical Profile
Ponatinib is a new multitargeted tyrosine kinase inhibitor (TKI) approved as an orphan drug under the FDA's accelerated approval program. It is indicated to treat patients with chronic-, accelerated-, or blast-phase chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior TKI therapy. CML and Ph+ALL are WBC cancers that affect more than 20,000 people in the United States. They are typically asymptomatic initially, but an enlarged spleen, fatigue, paleness from anemia, and disrupted thermoregulation may develop. Ponatinib is the third drug approved for CML treatment since 2012; the others are bosutinib (Bosulif) and omacetaxine (Synribo).
Approval of ponatinib was based on a single-arm, open-label, multicenter, phase II trial involving >449 patients with CML or Ph+ALL whose disease was resistant or intolerant to prior TKI therapy. Ponatinib 45 mg once daily resulted in a reduction in the percentage of cells expressing the Philadelphia chromosome genetic mutation (major cytogenetic response) in 54% of patients, including 70% of patients who also had a T315I mutation. Ponatinib also resulted in a normalization of WBC counts or no evidence of leukemia (major hematologic response) in 52% of accelerated-phase CML patients, 31% of blast-phase CML patients, and 41% of Ph+ALL patients.
Pharmacology and Pharmacokinetics
Ponatinib is an imidazo[1,2-b]pyridazine benzamide (Figure 1) that functions as a TKI. Its primary target is the breakpoint cluster region–Abelson (Bcr-Abl) tyrosine kinase expressed by CML and Ph+ALL, but it also targets Bcr-Abl isoforms that carry mutations, including the T315I mutation. Ponatinib also binds to members of the VEGFR, PDGFR, FGFR, and EPH receptors and SRC families of kinases, and to KIT, RET, TIE2, and FLT3.
(Enlarge Image)
Figure 1.
Ponatinib
The absolute bioavailability of ponatinib is unknown. The drug has a half-life of 24 hours, and it is >99% plasma protein bound. Ponatinib is metabolized by CYP3A4 and, to a lesser extent, by CYP2C8, 2D6, 3A5, and esterases and amidases. Approximately 64% of ponatinib is excreted as metabolites, primarily in the feces. Ponatinib does not inhibit metabolism of other CYP-substrate drugs, nor does it appear to induce CYP metabolism. It does, however, inhibit adenosine triphosphate–binding cassette (ABC) G2, the bile salt export pump, and the P-glycoprotein (Pgp) pump.
Adverse Reactions (ARs) and Drug Interactions
The most common ARs (≥20%) reported in clinical trials were myelosuppression (thrombocytopenia, neutropenia, leukopenia, anemia, and lymphopenia), hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Ponatinib also carries a Black Box Warning that the drug may cause arterial thrombosis and hepatotoxicity. The drug should be avoided in pregnancy because of its potential for fetal harm (Pregnancy Category D). Patients who breastfeed or intend to breastfeed should not use ponatinib.
The ponatinib dosage should be reduced when the drug is coadministered with CYP3A inhibitors. Coadministration of ponatinib with strong CYP3A inducers or drugs that elevate gastric pH (proton pump inhibitors, H2 blockers, antacids) may lead to inadequate drug concentration. Because of its inhibition of Pgp and ABC, ponatinib may result in altered efficacy of drugs that are sensitive substrates of these pumps; however, formal studies have not been conducted to determine the severity of this interaction.
Dosage and Administration
Ponatinib is supplied as 15-mg and 45-mg tablets. The recommended dosage is 45 mg once daily with or without food. The dosage should be reduced to 30 mg once daily when the drug is administered with strong CYP3A inhibitors. Ponatinib has not been studied in pediatric patients or in hepatically or renally impaired patients. Ponatinib therapy should be interrupted for 1 week prior to major surgery to avoid an increased bleeding risk. Patients taking ponatinib who experience myelosuppression, hepatic toxicity, asymptomatic lipase elevation (grade 3–4), or pancreatitis (grade 2–3) should interrupt therapy until toxicity subsides, then resume therapy at the dosage recommended by the manufacturer.
Source...