Effects of ketoconazole on the pharmacokinetics of ponatinib in healthy subjects

Area of Science:

• Pharmacology
• Oncology
• Drug Metabolism

Background:

• Ponatinib is a tyrosine kinase inhibitor (TKI) used for leukemia.
• In vitro studies indicate ponatinib is partly metabolized by CYP3A4.
• Drug interactions involving ponatinib and CYP3A4 inhibitors require investigation.

Purpose of the Study:

• To evaluate the effect of CYP3A4 inhibition on ponatinib pharmacokinetics.
• To assess the impact on the CYP3A4-mediated metabolite AP24567.
• To inform clinical recommendations for concurrent ponatinib and CYP3A4 inhibitor use.

Main Methods:

• A single-center, randomized, two-period, crossover study in healthy volunteers (N=22).
• Subjects received single oral doses of ponatinib 15 mg alone and with ketoconazole 400 mg daily for 5 days.
• Pharmacokinetic parameters including Cmax and AUC were measured.

Main Results:

• Coadministration with ketoconazole increased ponatinib AUC by 78% and Cmax by 47%.
• Exposure to the metabolite AP24567 decreased by 71% with ketoconazole.
• AP24567 exposure was minimal (<4% of ponatinib exposure) when ponatinib was given alone.

Conclusions:

• Concurrent use of ponatinib with strong CYP3A4 inhibitors necessitates caution due to increased ponatinib exposure.
• A reduction in the starting ponatinib dose from 45 mg to 30 mg daily could be considered when coadministered with strong CYP3A4 inhibitors.
• These findings support dose adjustment strategies to manage potential drug-drug interactions with ponatinib.