使用不同基于生理的药代动力学建模平台的单克隆抗体倾向预测的比较。

IF 2.2 4区 医学 Q3 PHARMACOLOGY & PHARMACY Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2024-12-01 Epub Date: 2023-11-12 DOI:10.1007/s10928-023-09894-4
Pieter-Jan De Sutter, Elke Gasthuys, An Vermeulen
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引用次数: 0

摘要

基于生理的药代动力学(PBPK)模型可用于利用生理和体外数据来预测血清和组织中的单克隆抗体(mAb)浓度。然而,目前尚不清楚跨PBPK建模平台对单抗处置的预测是否一致。在这项工作中,比较了三个平台(Simcyp、PK-Sim和GastroPlus)对IgG、阿达木单抗和英夫利昔单抗的PBPK模拟。使用从文献中收集的观察数据评估预测血清和组织浓度的准确性。还比较了生理和mAb相关的输入参数,并进行了敏感性分析,以评估输入值改变时模型的行为。当剂量为1 mg/kg时,不同平台间IgG血清动力学的差异很小,但在更高剂量(100 mg/kg)和参考(健康)生理输入值改变时,差异变得更加明显。阿达木单抗和英夫利昔单抗的预测血清浓度在不同平台上具有可比性,但明显高于观察值。组织浓度在平台之间有显著差异,无论是总的和间质液(ISF)浓度。除脑组织浓度被高估外,所有组织的总组织浓度的准确性都在观察值的三倍之内。组织ISF浓度的预测不太准确,最好由GastroPlus捕获。总的来说,这些模拟表明,不同的PBPK平台通常预测相似的单抗血清浓度,但不同的组织浓度。因此,在没有数据验证预测的情况下,使用PBPK模型模拟单克隆抗体的影响部位组织浓度时,需要谨慎。
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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Comparison of monoclonal antibody disposition predictions using different physiologically based pharmacokinetic modelling platforms.

Physiologically based pharmacokinetic (PBPK) models can be used to leverage physiological and in vitro data to predict monoclonal antibody (mAb) concentrations in serum and tissues. However, it is currently not known how consistent predictions of mAb disposition are across PBPK modelling platforms. In this work PBPK simulations of IgG, adalimumab and infliximab were compared between three platforms (Simcyp, PK-Sim, and GastroPlus). Accuracy of predicted serum and tissue concentrations was assessed using observed data collected from the literature. Physiological and mAb related input parameters were also compared and sensitivity analyses were carried out to evaluate model behavior when input values were altered. Differences in serum kinetics of IgG between platforms were minimal for a dose of 1 mg/kg, but became more noticeable at higher dosages (> 100 mg/kg) and when reference (healthy) physiological input values were altered. Predicted serum concentrations of both adalimumab and infliximab were comparable across platforms, but were noticeably higher than observed values. Tissue concentrations differed remarkably between the platforms, both for total- and interstitial fluid (ISF) concentrations. The accuracy of total tissue concentrations was within a three-fold of observed values for all tissues, except for brain tissue concentrations, which were overpredicted. Predictions of tissue ISF concentrations were less accurate and were best captured by GastroPlus. Overall, these simulations show that the different PBPK platforms generally predict similar mAb serum concentrations, but variable tissue concentrations. Caution is therefore warranted when PBPK models are used to simulate effect site tissue concentrations of mAbs without data to verify the predictions.

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来源期刊
CiteScore
4.90
自引率
4.00%
发文量
39
审稿时长
6-12 weeks
期刊介绍: Broadly speaking, the Journal of Pharmacokinetics and Pharmacodynamics covers the area of pharmacometrics. The journal is devoted to illustrating the importance of pharmacokinetics, pharmacodynamics, and pharmacometrics in drug development, clinical care, and the understanding of drug action. The journal publishes on a variety of topics related to pharmacometrics, including, but not limited to, clinical, experimental, and theoretical papers examining the kinetics of drug disposition and effects of drug action in humans, animals, in vitro, or in silico; modeling and simulation methodology, including optimal design; precision medicine; systems pharmacology; and mathematical pharmacology (including computational biology, bioengineering, and biophysics related to pharmacology, pharmacokinetics, orpharmacodynamics). Clinical papers that include population pharmacokinetic-pharmacodynamic relationships are welcome. The journal actively invites and promotes up-and-coming areas of pharmacometric research, such as real-world evidence, quality of life analyses, and artificial intelligence. The Journal of Pharmacokinetics and Pharmacodynamics is an official journal of the International Society of Pharmacometrics.
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