Department of Clinical Pharmacology, Genentech Inc, South San Francisco, California, USA.
Simulations Plus Inc, Lancaster, California, USA.
CPT Pharmacometrics Syst Pharmacol. 2017 Nov;6(11):747-755. doi: 10.1002/psp4.12228. Epub 2017 Oct 17.
Pictilisib, a weakly basic compound, is an orally administered, potent, and selective pan-inhibitor of phosphatidylinositol 3-kinases for oncology indications. To investigate the significance of high-fat food and gastric pH on pictilisib pharmacokinetics (PK) and enable label recommendations, a dedicated clinical study was conducted in healthy volunteers, whereby both top-down (population PK, PopPK) and bottom-up (physiologically based PK, PBPK) approaches were applied to enhance confidence of recommendation and facilitate the clinical development through scenario simulations. The PopPK model identified food (for absorption rate constant (K )) and proton pump inhibitors (PPI, for relative bioavailability (F ) and K ) as significant covariates. Food and PPI also impacted the variability of F . The PBPK model accounted for the supersaturation tendency of pictilisib, and gastric emptying physiology successfully predicted the food and PPI effect on pictilisib absorption. Our research highlights the importance of applying both quantitative approaches to address critical drug development questions.
比替利斯布是一种弱碱性化合物，是一种口服的、有效的、选择性的磷脂酰肌醇 3-激酶抑制剂，用于肿瘤适应证。为了研究高脂肪食物和胃 pH 值对比替利斯布药代动力学（PK）的影响，并为标签推荐提供依据，在健康志愿者中进行了一项专门的临床研究，通过自上而下（群体 PK，PopPK）和自下而上（基于生理的 PK，PBPK）的方法进行研究，以增强推荐的可信度，并通过情景模拟促进临床开发。PopPK 模型确定食物（吸收速率常数（K a ））和质子泵抑制剂（PPI，相对生物利用度（F ）和 K a ）为重要的协变量。食物和 PPI 也影响 F 的变异性。PBPK 模型解释了比替利斯布的过饱和趋势，胃排空生理学成功预测了食物和 PPI 对比替利斯布吸收的影响。我们的研究强调了应用定量方法解决关键药物开发问题的重要性。
