Dosing Recommendation Based on the Effects of Different Meal Types on Pexidartinib Pharmacokinetics in Healthy Subjects: Implementation of Model-informed Drug Development Strategy.

Abstract

Pexidartinib, an oral small molecule inhibitor of the colony-stimulating factor 1 receptor, is approved for treatment of adults with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable to improvement with surgery. The original dosing regimen is 400mg of pexidartinib (2×200-mg capsules) twice daily, administered on an empty stomach at least 1hour before or 2hours after a meal or snack. Because pexidartinib is likely to be taken over an extended period of time, the ability to take pexidartinib with a meal would simplify timing of administration and potentially improve compliance. Since administering 400mg of pexidartinib with alow-fatmeal increases exposure by ≈60% relative to the fasted state, administering 250mg of pexidartinib with a low-fatmeal (low-fat meal dosing regimen) was predicted to achieve an exposure similar to 400mg administered during a fasted state (original dosing regimen). Based on clinical trial simulations with two one-sided t-tests and bootstrapping (ie, resampling) analyses, a bioequivalence study (n=24) would have >90% power to conclude that the original dosing regimen (400mg fasted twice daily) and thelow-fatmeal dosing regimen (250mg with alow-fatmeal twice daily) are bioequivalent. This report provides the outcome of the implementation of the model-informed drug development strategy to recommend and justify alow-fatmeal dosing regimen for pexidartinib that has the potential to improve patient compliance while maintaining drug exposure.