Physiologically-based pharmacokinetic modeling to predict the exposure and provide dosage regimens of tacrolimus in pregnant women with infection disease

IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY European Journal of Pharmaceutical Sciences Pub Date : 2025-01-07 DOI:10.1016/j.ejps.2025.107003
Jianwen Xu , Guimu Guo , Shuifang Zhou , Han Wang , Yuewen Chen , Rongfang Lin , Pinfang Huang , Cuihong Lin
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Abstract

Tacrolimus is extensively used for the prevention of graft rejection following solid organ transplantation in pregnant women. However, knowledge gaps in the dosage of tacrolimus for pregnant patients with different CYP3A5 genotypes and infection conditions have been identified. This study aimed to develop a pregnant physiologically based pharmacokinetic (PBPK) model to characterize the maternal and fetal pharmacokinetics of tacrolimus during pregnancy and explore and provide dosage adjustments. We developed PBPK models for nonpregnant patients and validated them via data from previous clinical studies using PK-Sim and Mobi software. To extrapolate to pregnancy, we considered anatomical, physiological, and metabolic alterations and simulated tacrolimus by adding six groups of IL-6 concentrations (0, 5, 25, 50, 500, and 5000 pg/mL). Models were verified by assessing goodness-of-fit plots and ratios of predicted-to-observed pharmacokinetic parameters.
The developed PBPK models adequately describe the available clinical data; the fold errors of the predicted and observed values of the area under the curve and peak plasma concentration were between 0.59 and 1.64, and the average folding error and the absolute average folding error values for all concentration–time data points were 1.15 and 1.36, respectively. The simulation results indicated that the area under the steady-state concentration‒time curve and trough concentrations decreased from the first to the third trimester of pregnancy. The trough concentrations were not within the therapeutic range (4–11 ng/mL) in pregnant patients with the CYP3A5 genotype for most of the infection conditions and exceeded its effective concentration in all the CYP3A5 nonexpressers. Based on the model-derived dosing regimen, the tacrolimus trough concentration in pregnant patients with different CYP3A5 genotypes could fall into the therapeutic window, which provided a clinical practice reference for dosage adjustments during pregnancy.

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基于生理的药代动力学模型预测感染孕妇的他克莫司暴露并提供剂量方案。
他克莫司被广泛用于预防孕妇实体器官移植后的移植排斥反应。然而,对于不同CYP3A5基因型和感染情况的孕妇,他克莫司的剂量存在知识空白。本研究旨在建立基于妊娠生理的药代动力学(PBPK)模型,以表征妊娠期间他克莫司的母胎药代动力学,探索并提供剂量调整。我们为未怀孕的患者建立了PBPK模型,并使用PK-Sim和Mobi软件通过先前临床研究的数据对其进行了验证。为了推断妊娠,我们考虑了解剖、生理和代谢的变化,并通过添加六组IL-6浓度(0、5、25、50、500和5000 pg/mL)来模拟他克莫司。通过评估拟合优度图和预测与观察的药代动力学参数的比率来验证模型。开发的PBPK模型充分描述了现有的临床数据;曲线下面积和峰值血药浓度预测值和观测值的折叠误差在0.59 ~ 1.64之间,各浓度-时间数据点的平均折叠误差和绝对平均折叠误差分别为1.15和1.36。模拟结果表明,从妊娠早期到妊娠晚期,稳态浓度-时间曲线下的面积和谷浓度呈下降趋势。在大多数感染情况下,CYP3A5基因型孕妇的谷浓度不在治疗范围(4-11 ng/mL)内,而在所有CYP3A5非表达者中,谷浓度均超过其有效浓度。基于模型衍生的给药方案,不同CYP3A5基因型妊娠患者他克莫司谷浓度可落入治疗窗口,为妊娠期剂量调整提供临床实践参考。
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来源期刊
CiteScore
9.60
自引率
2.20%
发文量
248
审稿时长
50 days
期刊介绍: The journal publishes research articles, review articles and scientific commentaries on all aspects of the pharmaceutical sciences with emphasis on conceptual novelty and scientific quality. The Editors welcome articles in this multidisciplinary field, with a focus on topics relevant for drug discovery and development. More specifically, the Journal publishes reports on medicinal chemistry, pharmacology, drug absorption and metabolism, pharmacokinetics and pharmacodynamics, pharmaceutical and biomedical analysis, drug delivery (including gene delivery), drug targeting, pharmaceutical technology, pharmaceutical biotechnology and clinical drug evaluation. The journal will typically not give priority to manuscripts focusing primarily on organic synthesis, natural products, adaptation of analytical approaches, or discussions pertaining to drug policy making. Scientific commentaries and review articles are generally by invitation only or by consent of the Editors. Proceedings of scientific meetings may be published as special issues or supplements to the Journal.
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