Effects of ketoconazole on the pharmacokinetics of ponatinib in healthy subjects

Abstract

Ponatinib is a BCR-ABL tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia in patients resistant or intolerant to prior TKIs. In vitro studies suggested that metabolism of ponatinib is partially mediated by CYP3A4. The effects of CYP3A4 inhibition on the pharmacokinetics of ponatinib and its CYP3A4-mediated metabolite, AP24567, were evaluated in a single-center, randomized, two-period, two-sequence crossover study in healthy volunteers. Subjects (N = 22) received two single doses (orally) of ponatinib 15 mg, once given alone and once coadministered with daily (5 days) ketoconazole 400 mg, a CYP3A4 inhibitor. Ponatinib plus ketoconazole increased ponatinib maximum plasma concentration (C(max)) and area under the concentration-time curve (AUC) compared with ponatinib alone. The estimated mean ratios for AUC0-∞, AUC0-t, and C(max) indicated increased exposures to ponatinib of 78%, 70%, and 47%, respectively; exposure to AP24567 decreased by 71%. Exposure to AP24567 was marginal after ponatinib alone (no more than 4% of the exposure to ponatinib). These results suggest that caution should be exercised with the concurrent use of ponatinib and strong CYP3A4 inhibitors and that a ponatinib dose decrease to 30 mg daily, from the 45 mg daily starting dose, could be considered.

Keywords: BCR-ABL; ketoconazole; pharmacokinetics; ponatinib; tyrosine kinase inhibitor.

Figure 1

Mean (±SD) ponatinib plasma concentrations (logarithmic scale) versus time for ponatinib alone and ponatinib + ketoconazole. Ponatinib was administered as a single oral 15-mg dose, once given alone and once coadministered with daily doses of ketoconazole 400 mg, for 5 days. The dashed line depicts the lower limit of quantitation (LOQ) for ponatinib (0.5 ng/mL), and the dotted line represents the 40 nM threshold concentration sufficient to inhibit all BCR-ABL mutants tested and to suppress the emergence of mutant clones in preclinical mutagenesis assays. Error bars represent the standard deviation (SD).

Figure 2

Mean (±SD) AP24567 plasma concentrations (logarithmic scale) versus time for ponatinib alone and ponatinib + ketoconazole. Ponatinib was administered as a single oral 15-mg dose, once given alone and once coadministered with daily doses of ketoconazole 400 mg, for 5 days. The dashed line depicts the lower limit of quantitation (LOQ) for AP24567 (0.1 ng/mL). Error bars represent the standard deviation (SD).