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 400 mg of pexidartinib (2 × 200-mg capsules) twice daily, administered on an empty stomach at least 1 hour before or 2 hours 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 400 mg of pexidartinib with a low-fat meal increases exposure by ≈60% relative to the fasted state, administering 250 mg of pexidartinib with a low-fat meal (low-fat meal dosing regimen) was predicted to achieve an exposure similar to 400 mg 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 (400 mg fasted twice daily) and the low-fat meal dosing regimen (250 mg with a low-fat meal twice daily) are bioequivalent. This report provides the outcome of the implementation of the model-informed drug development strategy to recommend and justify a low-fat meal dosing regimen for pexidartinib that has the potential to improve patient compliance while maintaining drug exposure.

Physiologically Based Pharmacokinetic Absorption Model for Pexidartinib to Evaluate the Impact of Meal Contents and Intake Timing on Drug Exposure

“…Food-effect studies conducted in healthy volunteers found that pexidartinib exposure increases with food consumption and approximately doubles when administered with an HFM over a dose range of 400-1800 mg; C max, AUC inf , and AUC from time 0 to the last quantifiable concentration all increased by approximately 100% with an HFM over this dose range. 11 Similarly, administration of 400-mg pexidartinib with an LFM, compared with the fasted state, resulted in a 56% increase in C max and a 59% increase in AUC inf . There was also a 71% increase in C max and a 66% increase in AUC inf for 200-mg pexidartinib administered with an LFM compared with 400-mg pexidartinib administered in a fasted state, dose normalized to 200 mg. 11 Using this information, it was estimated that the daily dose needed for administration of pexidartinib with an LFM is 500 mg to achieve equivalent exposure to an 800-mg daily dose administered on an empty stomach.…”

“…11 Similarly, administration of 400-mg pexidartinib with an LFM, compared with the fasted state, resulted in a 56% increase in C max and a 59% increase in AUC inf . There was also a 71% increase in C max and a 66% increase in AUC inf for 200-mg pexidartinib administered with an LFM compared with 400-mg pexidartinib administered in a fasted state, dose normalized to 200 mg. 11 Using this information, it was estimated that the daily dose needed for administration of pexidartinib with an LFM is 500 mg to achieve equivalent exposure to an 800-mg daily dose administered on an empty stomach. This was confirmed using a model-informed bioequivalence study, in which clinical trial simulations showed that the use of 250-mg pexidartinib administered twice daily with an LFM would have an exposure similar to the original regimen of 400 mg administered twice daily on an empty stomach.…”

“…12,13 Therefore, it is important to understand the effects of meal contents and meal timing on the PK of pexidartinib. Pexidartinib absorption is influenced by the fat content of meals due to the presence of bile and delayed gastric emptying 11 ; therefore, consumption of an HFM within hours of pexidartinib dosing with an LFM could potentially influence pexidartinib exposure. Furthermore, while parameters in clinical trials are strictly controlled, a greater variation in the timing and content of meals is more likely with real-world use of pexidartinib.…”

“…4 However, foodeffect studies conducted in healthy volunteers showed that pexidartinib exposure increases by approximately 60% with a low-fat meal (LFM; 400-500 kcal and 25% of calories derived from fat) and approximately 100% with a high-fat meal (HFM; 800-1000 kcal and approximately 50% of calories from fat). 11 A model-informed bioequivalence study concluded with greater than 90% power that the original dosing regimen (400 mg fasted twice daily) and the LFM dosing regimen (250 mg with an LFM) were equivalent. 11 These findings supported a change in the dosing regimen of pexidartinib to 250 mg (2 × 125-mg capsules) twice daily with an LFM (approximately 11-14 g of total fat).…”

“…11 A model-informed bioequivalence study concluded with greater than 90% power that the original dosing regimen (400 mg fasted twice daily) and the LFM dosing regimen (250 mg with an LFM) were equivalent. 11 These findings supported a change in the dosing regimen of pexidartinib to 250 mg (2 × 125-mg capsules) twice daily with an LFM (approximately 11-14 g of total fat). The dosing change was made due to the known effects of food on the absorption of pexidartinib and the potential for drug overexposure; as such, the dosing change has the potential to improve patient compliance and reduce the risk of potential side effects, including hepatotoxicity.…”