Food and Drug Administration (FDA), Office of Clinical Pharmacology, 10903 New Hampshire Ave, Silver Spring, Maryland, 20993, USA.
College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, Michigan, 48109, USA.
AAPS J. 2020 Sep 27;22(6):124. doi: 10.1208/s12248-020-00509-1.
Many orally administered drugs with negative food effects (i.e., lower exposure under fed conditions) are often primarily or partially eliminated by biliary excretion. The aim of this study is to assess the potential correlation between a negative food effect and biliary excretion. Correlation analysis was conducted using a training dataset containing 27 drugs which met the following criteria: (1) immediate-release formulations, (2) shows a negative food effect, (3) > 10% biliary clearance, and (4) does not undergo extensive metabolism. A correlation between fed-state biliary clearance (CL) and fasted-state biliary clearance (CL) (y = 1.81*x, R = 0.68) was observed. The 1.8-fold increase in biliary clearance was then used as a correction factor to improve physiologically based pharmacokinetic (PBPK) prediction of food effects for 12 test drugs. The mean deviations of predicted fed/fasting AUC ratio and C ratio from clinically observed values were reduced from 32.4 to 17.2% and from 63.3 to 54.3%, respectively. In contrast to the positive food effects on most biopharmaceutics classification system (BCS) class II drugs for which food-stimulated bile flow increases drug solubility and absorption, our results suggest that the elimination of biliary excreted drugs is increased by food-stimulated bile flow, resulting in negative food effects.
许多具有负食物效应（即进食状态下暴露量降低）的口服药物主要或部分通过胆汁排泄消除。本研究旨在评估负食物效应与胆汁排泄之间的潜在相关性。采用包含 27 种药物的训练数据集进行相关性分析，这些药物符合以下标准：（1）速释制剂，（2）具有负食物效应，（3）>10%胆汁清除率，（4）不经历广泛代谢。观察到进食状态下胆汁清除率（CL）与空腹状态下胆汁清除率（CL）之间的相关性（y=1.81*x，R=0.68）。然后，将胆汁清除率增加 1.8 倍作为校正因子，以改善 12 种受试药物的基于生理的药代动力学（PBPK）预测食物效应。与临床观察值相比，预测的进食/空腹 AUC 比值和 C 比值的平均偏差从 32.4%降至 17.2%，从 63.3%降至 54.3%。与大多数生物药剂学分类系统（BCS）II 类药物的正食物效应相反，这些药物的进食刺激胆汁流增加了药物的溶解度和吸收，我们的结果表明，胆汁排泄药物的消除因进食刺激胆汁流而增加，导致负食物效应。
