C. Xu,1 E. Shamiyeh,1 V. Kanamaluru,1 L. von Moltke,2 B. Vince,3 M. Zhang1; 1Sanofi, Bridgewater, NJ, 2Sanofi, Cambridge, MA, 3Vince & Associates Clinical Research, Overland Park, KS
BACKGROUND: Fedratinib, a JAK2-selective inhibitor, was in clinical development as a treatment for myelofibrosis. It exhibited pH-dependent solubility, with optimum solubility being at acid pH. Pantoprazole, a gastric pH modifier via proton pump inhibition, was used as a probe to evaluate the effect of an increase in gastric pH on the absorption of fedratinib.
METHODS: A phase I, single-center, open-label, two-period, two-treatment, fixed-sequence crossover study with a minimum 14 day washout period was conducted to assess the effect of 7-day repeated oral 40 mg doses of pantoprazole on the pharmacokinetics of fedratinib, following 500 mg single oral dose. Twenty-six healthy adult males received 2 single 500 mg doses of SAR302503, with 1 dose administered alone on Day 1 of Period 1 and 1 dose administered with pantoprazole on Day 7 of Period 2. Blood samples for fedratinib PK were collected up to 168 hours post-dose in each Period. A validated LC‑MS/MS method was used to determine the plasma concentrations of fedratinib.
RESULTS: Administration of repeated 40 mg QD oral doses of pantoprazole with a single oral dose of 500 mg fedratinib to healthy male subjects resulted in a treatment ratio of 1.09 (90%CI: 0.95 to 1.25) for Cmax and 1.15 (90%CI: 1.04 to 1.27) for AUC. Fedratinib was generally tolerated in healthy male subjects at 500 mg after single oral doses and after 7 daily doses of pantoprazole. Safety profile of fedratinib was consistent with previous findings.
CONCLUSION: Coadministration of 40 mg repeated once daily oral doses of pantoprazole with a 500 mg single oral dose of fedratinib, a gastric pH modifier, did not significantly affect the pharmacokinetics of fedratinib.