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.
摘要：
佩西达替尼，一种口服集落刺激因子1受体的小分子抑制剂，已被批准用于治疗成人症状性腱鞘巨细胞瘤，伴有严重的发病率或功能限制，并且不能通过手术改善。最初的给药方案是400毫克的帕西达替尼（2×200毫克胶囊），每天两次，在餐前至少1小时或餐后2小时空腹给药或零食。因为帕西达替尼可能会在很长一段时间内服用，与餐食一起服用帕西达替尼的能力将简化给药时间,并可能改善依从性.由于400mg帕西达替尼与低脂膳食一起使用，相对于禁食状态，暴露量增加约60%，在低脂膳食(低脂膳食给药方案)的同时给予250mg帕西达替尼,预测其暴露量与在禁食状态(原始给药方案)期间给予400mg相似.基于具有两个单侧t检验和自举的临床试验模拟(即，重采样)分析，生物等效性研究(n=24)将有>90%的功效得出结论:原始给药方案(每天两次禁食400mg)和低脂膳食给药方案(每天两次低脂膳食250mg)是生物等效的.本报告提供了实施基于模型的药物开发策略的结果，以推荐和证明帕西达替尼的低脂膳食给药方案具有改善患者依从性的潜力，同时保持药物暴露。
