Results of a pharmacokinetic study conducted in healthy people revealed a drug-drug interaction between ketoconazole and fedratinib, an agent indicated for certain patients with myelofibrosis. These findings were reported in Cancer Chemotherapy and Pharmacology.1
An oral tyrosine kinase inhibitor, fedratinib was approved by the US Food and Drug Administration (FDA) in 2019 for the treatment of adult patients with intermediate-2 and high-risk primary or secondary myelofibrosis, a Philadelphia chromosome-negative myeloproliferative neoplasm.2 It is a selective inhibitor of the JAK2 kinase in the setting of both mutated and unmutated forms of the JAK2 gene, and has also been shown to have activity against the FLT3 kinase.
Results of in vitro studies have shown that fedratinib is metabolized by cytochrome P450 enzymes, particularly CYP3A4, which are also involved in the metabolism of many other drugs. Hence, a central aim of this study was to evaluate the pharmacokinetics of fedratinib in healthy persons in the presence of ketoconazole, a strong inhibitor of CYP3A4.
This open-label, nonrandomized study included 2 cohorts of 7 healthy, non-obese male participants who received different doses of fedratinib: cohort 1 received 50 mg and cohort 2 received 300 mg.
Following a screening interval, the study design included 2 separate, consecutive periods in which participants in both cohorts received a single dose of fedratinib, alone (period 1) and in combination with ketoconazole administered at a dose of 200 mg twice daily (period 2). The durations of periods 1 and 2 were 9 days and 15 days, respectively, with fedratinib administered on day 1 of period 1 and day 6 of period 2. Two days separated periods 1 and 2. Ketoconazole was administered on days 1 through 14 of period 2 (study days 11 through 24), and a final study visit was conducted 7 to 10 days after the final dose of ketoconazole was administered (study days 32 to 35).
Fedratinib was administered in the morning on an empty stomach, and no food was allowed for 4 hours following its administration. In contrast, ketoconazole was administered to participants in the fed state, except when coadministered with fedratinib to fasted participants.
A key finding from this study was that fedratinib exposure, as measured by the area under the plasma concentration-time curve from zero to infinity, increased by more than 3-fold when a single dose of either 50 mg or 300 mg was co-administered with ketoconazole.
Regarding the safety of fedratinib administered alone or in combination with a steady-state concentration of ketoconazole, no serious or severe treatment-emergent adverse events (TEAEs) were observed in either setting for either cohort. Of the mild/moderate TEAEs observed in 5 patients receiving 300 mg of fedratinib in the presence of ketoconazole, only 1 was classified as moderate and all TEAEs had resolved by the final study visit.
“These results suggest that strong CYP3A4 inhibitors that increase fedratinib plasma concentrations need to be used with caution. In place of a strong CYP3A4 inhibitor, alternative therapies that do not strongly inhibit CYP3A4 activity should be considered when coadministering with fedratinib,” the study authors noted in their concluding comments.
1. Ogasawara K, Xu C, Kanamaluru V, Palmisano M, Krishna G. Effects of repeated oral doses of ketoconazole on a sequential ascending single oral dose of fedratinib in healthy subjects [published online April 4, 2020]. Cancer Chemother Pharmacol. doi: 10.1007/s00280-020-04067-3
2. Fedratinib [package insert]. Summit, NJ: Celgene Corporation; 2019.