Burmeister Getz Elise, Niglis Séverine, Papadimitriou Athanasia, Statelova Marina, Ren Xiaojun, Nakhla Keroles, Sharaby Sherif, Tariq Muzammil, Garbuio Luca, Bakhsh Sumerah
Biomedical Research, Novartis, 5959 Horton St, Emeryville, CA, 94608, USA.
Novartis Pharma AG, Basel, Switzerland.
AAPS PharmSciTech. 2025 Apr 30;26(5):121. doi: 10.1208/s12249-025-03109-4.
Alpelisib, an oral α-specific phosphoinositide 3-kinase (PI3K) inhibitor, has been shown to be safe and effective for some patients with gain-of-function mutation in the PIK3CA oncogene. Alpelisib has received US FDA accelerated approval as Vijoice® film-coated tablets to treat severe PIK3CA-Related Overgrowth Spectrum (PROS). PROS typically displays clinical manifestations in the first year of patient life. Therefore, oral granules were developed as an age-appropriate pediatric dosage form. Bioequivalence between alpelisib granules and tablet and the effect of food on granules pharmacokinetics were assessed in a single-center, randomized, three-treatment, six-sequence, three-period, crossover study among 60 healthy adults. Participants were randomly assigned to receive a single 50-mg alpelisib dose as: (i) tablet following a meal, (ii) granules following a meal, and (iii) granules while fasting. Statistical analysis of non-compartmental pharmacokinetic parameters demonstrated bioequivalence between the 50-mg alpelisib granules and tablet forms when administered with food: estimated geometric mean ratios (90% confidence interval) for granules-versus-tablet area under the curve (AUC) from time zero to infinity (AUC), to the last measurable concentration (AUC) and maximum observed concentration (C) were 0.984 (0.952, 1.02), 0.980 (0.946, 1.02), and 0.947 (0.891, 1.01), respectively. No clinically relevant food effect on 50-mg alpelisib granules pharmacokinetics was observed. These results were accurately predicted using physiologically based biopharmaceutical modeling. Alpelisib granules provide a bioequivalent alternative to tablets for patients prescribed a 50-mg dose and have difficulty swallowing tablets, an important consideration for convenience and compliance of this standard-of-care chronic therapy for patients with PROS. This study was registered in ClinicalTrials.gov on January 4, 2022 (NCT05195892).
阿哌利西布是一种口服的α特异性磷酸肌醇3激酶（PI3K）抑制剂，已被证明对一些携带PIK3CA致癌基因功能获得性突变的患者安全有效。阿哌利西布已获得美国食品药品监督管理局（FDA）的加速批准，以维择®薄膜包衣片的形式用于治疗严重的PIK3CA相关过度生长谱系疾病（PROS）。PROS通常在患者生命的第一年就表现出临床表现。因此，开发了口服颗粒剂作为适合儿童年龄的剂型。在一项针对60名健康成年人的单中心、随机、三治疗组、六序列、三周期交叉研究中，评估了阿哌利西布颗粒剂与片剂之间的生物等效性以及食物对颗粒剂药代动力学的影响。参与者被随机分配接受单次50毫克阿哌利西布剂量，方式如下：（i）餐后服用片剂，（ii）餐后服用颗粒剂，（iii）空腹服用颗粒剂。对非房室药代动力学参数的统计分析表明，50毫克阿哌利西布颗粒剂与片剂在与食物一起服用时具有生物等效性：颗粒剂与片剂从零时间到无穷大的曲线下面积（AUC）、到最后可测量浓度的AUC以及最大观察浓度（C）的估计几何平均比值（90%置信区间）分别为0.984（0.952，1.02）、0.980（0.946，1.02）和0.947（0.891，1.01）。未观察到食物对50毫克阿哌利西布颗粒剂药代动力学有临床相关影响。使用基于生理的生物药剂学模型准确预测了这些结果。对于规定服用50毫克剂量且吞咽片剂有困难的患者，阿哌利西布颗粒剂为片剂提供了生物等效的替代选择，这对于PROS患者这种标准治疗慢性疗法的便利性和依从性来说是一个重要考虑因素。本研究于2022年1月4日在ClinicalTrials.gov上注册（NCT05195892）。
