Distribution

Ponatinib is greater than 99% bound to plasma proteins in vitro. The geometric mean (CV%) apparent steady state volume of distribution is 1223 liters (102%) following oral administration of Iclusig 45 mg once daily for 28 days in patients with cancer. Ponatinib is a weak substrate for both P-gp and ABCG2 [also known as BCRP] in vitro. Ponatinib is not a substrate for organic anion transporting polypeptides (OATP1B1, OATP1B3) and organic cation transporter 1 (OCT1) in vitro.

Metabolism

At least 64% of a ponatinib dose undergoes phase I and phase II metabolism. CYP3A4 and to a lesser extent CYP2C8, CYP2D6 and CYP3A5 are involved in the phase I metabolism of ponatinib in vitro. Ponatinib is also metabolized by esterases and/or amidases.

Elimination

The geometric mean (range) terminal elimination half-life of ponatinib was approximately 24 (12 to 66) hours following Iclusig 45 mg oral administration once daily for 28 days in patients with cancer. Exposure increased by approximately 90% (median) [range: 20% to 440%] between the first dose and presumed steady state. Ponatinib is mainly eliminated via feces. Following a single oral dose of [14C]-labeled ponatinib, approximately 87% of the radioactive dose is recovered in the feces and approximately 5% in the urine.

Drug Interactions

Coadministration of Ponatinib and CYP3A Inhibitors

Coadministration of a single 15 mg oral dose of ponatinib in the presence of ketoconazole (400 mg daily), a strong CYP3A inhibitor to 22 healthy volunteers, increases the AUC0-∞ and Cmax of ponatinib by 78% and 47%, respectively, when compared to administration of ponatinib alone [see Drug Interactions (7.1)].

Coadministration of Ponatinib and CYP3A Inducers

Since the human oxidative metabolism of ponatinib via the cytochrome P450 system primarily involves CYP3 isozymes, a reduction in ponatinib exposure is likely and was observed in simulations using a mechanistic model [see Drug Interactions (7.2)].

Coadministration With Other CYP Substrates

In vitro studies indicate that ponatinib does not inhibit the metabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A, or CYP2D6 and does not induce the metabolism of substrates for CYP1A2, CYP2B6, or CYP3A.

Coadministration With Substrates of Transporters

In vitro, ponatinib is an inhibitor of P-gp and ABCG2 [also known as BCRP], and BSEP [see Drug Interactions (7.4)].

In vitro, ponatinib did not inhibit the human organic anion transporting polypeptides OATP1B1 or OATP1B3, or the organic cation transporters OCT1, OCT2, OAT1, and OAT3.

Pharmacokinetics in Specific Populations

Hepatic Impairment

Iclusig has not been studied in patients with hepatic impairment. As hepatic elimination is a major route of excretion for ponatinib, hepatic impairment may result in increased plasma ponatinib concentrations [see Use in Specific Populations (8.6)].

Renal Impairment

Iclusig has not been studied in patients with renal impairment. Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined [see Use in Specific P