Evaluation of the effect of multiple doses of rifampin on the pharmacokinetics and safety of ponatinib in healthy subjects.

Ponatinib, an oral tyrosine kinase inhibitor with significant activity in heavily pretreated patients with chronic myeloid leukemia, is a CYP3A4 substrate. This open-label, nonrandomized, fixed-order crossover study evaluated the effect of multiple oral doses of rifampin, a strong CYP3A4 inducer, on the pharmacokinetics of ponatinib (45 mg, single dose). Twenty healthy adults received ponatinib on day 1, rifampin 600 mg alone on days 8-13, 15, and 16, and rifampin 600 mg with ponatinib on day 14. Rifampin decreased maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) from time zero to time of last measurable concentration (AUC0-t ) and from time zero to infinity (AUC0-∞ ) of ponatinib by 42%, 59%, and 63%, respectively, with no effect on time to Cmax . The limits of the 90% confidence intervals of the estimated geometric mean ratios of ponatinib Cmax , AUC0-t , and AUC0-∞ did not fall within the 80-125% margins for equivalence, suggesting a statistically significant interaction. Coadministration of ponatinib with strong CYP3A4 inducers should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure, because the safety of ponatinib dose increases has not been studied in this context.