Evaluation of Solubility-Limited Absorption as a Surrogate to Predicting Positive Food Effect of BCS II/IV Drugs.

IF 4 2区医学 Q1 PHARMACOLOGY & PHARMACY

Clinical Pharmacokinetics Pub Date : 2025-03-01 Epub Date: 2025-02-03 DOI:10.1007/s40262-025-01473-9

Karine Rodriguez-Fernandez, José David Gómez-Mantilla, Suneet Shukla, Peter Stopfer, Peter Sieger, Victor Mangas-Sanjuán, Sheila Annie Peters

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引用次数: 0

Abstract

Introduction and objective: Physiologically based pharmacokinetic (PBPK) models are increasingly used to predict food effect (FE) but model parameterization is challenged by in vitro-in vivo (IVIV) disconnect and/or parameter nonidentifiability. To overcome these issues, we propose a simplified PBPK model, in which all solubility-driven processes are lumped into a single parameter, solubility, which is optimized against observed concentration-time data.

Methods: A set of commercially available biopharmaceutical classification system (BCS) II/IV compounds was selected to measure the solubility in a fasted state simulated intestinal fluid (FaSSIF) medium. The compounds were ranked from the lowest to the highest dose-adjusted FaSSIF solubility (FaSSIF/D) value and subdivided into three areas based on an upper and a lower limit: drugs with FaSSIF/D > upper limit having no FE, drugs with FaSSIF/D < lower limit having FE, and drugs between the limits said to be in the sensitivity range (SR), for which we tested the hypothesis that solubility-limited absorption (SLA) identified by simplified PBPK model can reliably predict positive FE if their exposures are not impacted by gut efflux or gut metabolism.

Results: We demonstrate, using a subset of drugs within SR for which PBPK models were available, that drugs with SLA exhibited a positive FE, while those with no SLA did not show FE.

Conclusions: This proposal allows for a reliable binary prediction of FE to enable timely decisions on the need for pilot FE studies as well as the timing of pivotal FE studies.

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评价溶解度限制吸收作为预测BCS II/IV药物的积极食物效应的替代指标。

基于生理的药代动力学（PBPK）模型越来越多地用于预测食物效应（FE），但模型参数化受到体内外（IVIV）断开和/或参数不可识别的挑战。为了克服这些问题，我们提出了一个简化的PBPK模型，其中所有溶解度驱动的过程都集中在一个参数中，溶解度，并根据观察到的浓度-时间数据进行优化。方法：选择一组市售生物制药分类系统（BCS） II/IV化合物，测定其在禁食状态模拟肠液（FaSSIF）培养基中的溶解度。这些化合物按剂量调整后的FaSSIF溶解度（FaSSIF/D）值从最低到最高排序，并根据上限和下限细分为三个区域：FaSSIF/D上限为>的药物无FE， FaSSIF/D <下限的药物有FE，以及在灵敏度范围（SR）之间的药物，我们检验了通过简化PBPK模型确定的溶解度限制吸收（SLA）的假设，如果它们的暴露不受肠道外排或肠道代谢的影响，可以可靠地预测FE阳性。结果：我们证明，使用SR中可获得PBPK模型的药物子集，具有SLA的药物表现出阳性的FE，而没有SLA的药物则不表现出FE。结论：该建议允许对FE进行可靠的二元预测，以便及时决定是否需要进行先导FE研究以及关键FE研究的时间。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical Pharmacokinetics 医学-药学

CiteScore

8.80

自引率

4.40%

发文量

审稿时长

6-12 weeks

期刊介绍： Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.