Ponatinib - How It Works
Clinical pharmacology details from the US FDA-approved label: how Ponatinib works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Ponatinib is a kinase inhibitor. Ponatinib inhibited the in vitro tyrosine kinase activity of ABL and T315I mutant ABL with IC 50 concentrations of 0.4 nM and 2.0 nM, respectively. Ponatinib inhibited the in vitro activity of additional kinases with IC 50 concentrations between 0.1 nM and 20 nM, including members of the VEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, TIE2, and FLT3. Ponatinib inhibited the in vitro viability of cells expressing native or mutant BCR::ABL, including T315I. In mice, treatment with ponatinib reduced the size of tumors expressing native or T315I mutant BCR::ABL when compared to controls.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ponatinib is a kinase inhibitor.
Ponatinib inhibited the in vitro tyrosine kinase activity of ABL and T315I mutant ABL with IC 50 concentrations of 0.4 nM and 2.0 nM, respectively.
Ponatinib inhibited the in vitro activity of additional kinases with IC 50 concentrations between 0.1 nM and 20 nM, including members of the VEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, TIE2, and FLT3.
Ponatinib inhibited the in vitro viability of cells expressing native or mutant BCR::ABL, including T315I.
In mice, treatment with ponatinib reduced the size of tumors expressing native or T315I mutant BCR::ABL when compared to controls.
12.2 Pharmacodynamics In PACE, the dose intensity-safety relationship indicated that there are significant increases in Grade ≥3 adverse reactions (hypertension, thrombocytopenia, pancreatitis, neutropenia, rash, ALT increase, AST increase, lipase increase, myelosuppression) over the dose range of 15 mg to 45 mg.
In addition to dose, increased age and history of ischemia, hypertension, diabetes, or hypercholesterolemia were also contributory factors to a higher incidence of AOEs.
In OPTIC, an exposure-response relationship between ponatinib exposure and molecular response rate at 12 months was observed.
A relationship between higher ponatinib exposures and higher incidence of adverse reactions, including thrombocytopenia (Grade ≥3) and AOEs, was observed.
In vitro, there was no significant inhibition of platelet aggregation with ponatinib at concentrations seen clinically and up to 0.7 mcg/mL (1.23 μM).
Cardiac Electrophysiology The QT interval prolongation potential of ICLUSIG was assessed in 39 patients with cancer who received ICLUSIG 30 mg, 45 mg, or 60 mg (0.67 to 1.33 times the approved maximum recommended starting dose) orally once daily.
No large mean increase (i.e., >20 msec) in QTc interval was detected.
12.3 Pharmacokinetics Ponatinib administered to patients with cancer exhibited approximately dose proportional increases in both steady-state C max and AUC over the dose range of 2 mg to 60 mg (0.04 to 1.33 times the approved maximum recommended starting dose).
The mean (CV%) C max and AUC( 0-24 ) of ICLUSIG 45 mg orally once daily at presumed steady-state in patients with advanced hematologic malignancies were 73 ng/mL (74%) and 1253 ng∙hr/mL (73%), respectively.
The mean (CV%) C max and AUC( 0-24 ) of ICLUSIG 30 mg orally once daily at presumed steady-state in patients with advanced hematologic malignancies were 65 ng/mL (28%) and 1080 ng∙hr/mL (29%), respectively.
Exposure increased by approximately 90% (median) [range: 20% to 440%] between the first dose and presumed steady-state.
Absorption The absolute bioavailability of ponatinib is unknown.
Peak concentrations of ponatinib are observed within 6 hours after ICLUSIG oral administration.
Effect of Food Following ingestion of either a high-fat (approximately 900 to 1000 calories with approximately 150, 250, and 500 to 600 calories derived from protein, carbohydrate, and fat, respectively) or low-fat meal (approximately 547 calories with approximately 56, 428 and 63 calories derived from protein, carbohydrate, and fat, respectively) by 22 healthy volunteers, plasma ponatinib exposures (AUC and C max ) were not different when compared to fasting conditions.
Distribution Ponatinib is greater than 99% bound to plasma proteins in vitro.
Pharmacokinetics
12.3 Pharmacokinetics Ponatinib administered to patients with cancer exhibited approximately dose proportional increases in both steady-state C max and AUC over the dose range of 2 mg to 60 mg (0.04 to 1.33 times the approved maximum recommended starting dose). The mean (CV%) C max and AUC( 0-24 ) of ICLUSIG 45 mg orally once daily at presumed steady-state in patients with advanced hematologic malignancies were 73 ng/mL (74%) and 1253 ng∙hr/mL (73%), respectively. The mean (CV%) C max and AUC( 0-24 ) of ICLUSIG 30 mg orally once daily at presumed steady-state in patients with advanced hematologic malignancies were 65 ng/mL (28%) and 1080 ng∙hr/mL (29%), respectively. Exposure increased by approximately 90% (median) [range: 20% to 440%] between the first dose and presumed steady-state. Absorption The absolute bioavailability of ponatinib is unknown. Peak concentrations of ponatinib are observed within 6 hours after ICLUSIG oral administration. Effect of Food Following ingestion of either a high-fat (approximately 900 to 1000 calories with approximately 150, 250, and 500 to 600 calories derived from protein, carbohydrate, and fat, respectively) or low-fat meal (approximately 547 calories with approximately 56, 428 and 63 calories derived from protein, carbohydrate, and fat, respectively) by 22 healthy volunteers, plasma ponatinib exposures (AUC and C max ) were not different when compared to fasting conditions. Distribution Ponatinib is greater than 99% bound to plasma proteins