Department of Pharmacy, University of Athens, Panepistimiopolis Zografou, 15784 Athens, Greece.
Pharma-Informatics Unit, Athena Research Center, Artemidos 6 & Epidavrou, 15125 Marousi, Greece.
J Antimicrob Chemother. 2024 Jun 3;79(6):1362-1371. doi: 10.1093/jac/dkae109.
To develop physiologically based pharmacokinetic (PBPK) models for widely used anti-TB drugs, namely rifampicin, pyrazinamide, isoniazid, ethambutol and moxifloxacin lung pharmacokinetics (PK)-regarding both healthy and TB-infected tissue (cellular lesion and caseum)-in preclinical species and to extrapolate to humans.
Empirical models were used for the plasma PK of each species, which were connected to multicompartment permeability-limited lung models within a middle-out PBPK approach with an appropriate physiological parameterization that was scalable across species. Lung's extracellular water (EW) was assumed to be the linking component between healthy and infected tissue, while passive diffusion was assumed for the drug transferring between cellular lesion and caseum.
In rabbits, optimized unbound fractions in intracellular water of rifampicin, moxifloxacin and ethambutol were 0.015, 0.056 and 0.08, respectively, while the optimized unbound fractions in EW of pyrazinamide and isoniazid in mice were 0.25 and 0.17, respectively. In humans, all mean extrapolated daily AUC and Cmax values of various lung regions were within 2-fold of the observed ones. Unbound concentrations in the caseum were lower than unbound plasma concentrations for both rifampicin and moxifloxacin. For rifampicin, unbound concentrations in cellular rim are slightly lower, while for moxifloxacin they are significantly higher than unbound plasma concentrations.
The developed PBPK approach was able to extrapolate lung PK from preclinical species to humans and to predict unbound concentrations in the various TB-infected regions, unlike empirical lung models. We found that plasma free drug PK is not always a good surrogate for TB-infected tissue unbound PK.
为广泛应用于抗结核药物（利福平、吡嗪酰胺、异烟肼、乙胺丁醇和莫西沙星）的生理相关药代动力学（PBPK）模型建立一个基于组织（细胞病变和干酪样坏死）的肺药代动力学（PK）模型，用于临床前动物模型和人类。
使用经验模型来描述每种药物在血浆中的 PK，然后通过中间-out PBPK 方法，将这些模型与多室渗透率受限的肺模型相连接，采用适当的生理参数化，使模型能够在不同物种之间进行扩展。肺细胞外液（EW）被认为是健康组织和感染组织之间的连接成分，而药物在细胞病变和干酪样坏死之间的转移则被认为是被动扩散。
在兔中，利福平、莫西沙星和乙胺丁醇在细胞内水中的优化未结合分数分别为 0.015、0.056 和 0.08，而在鼠中吡嗪酰胺和异烟肼在 EW 中的优化未结合分数分别为 0.25 和 0.17。在人类中，各种肺区域的平均预测每日 AUC 和 Cmax 值都在观察值的 2 倍以内。干酪样坏死中的游离药物浓度低于游离血浆浓度，对于利福平而言，细胞边缘的游离浓度略低，而对于莫西沙星而言，游离浓度显著高于游离血浆浓度。
与经验肺模型不同，所开发的 PBPK 方法能够从临床前动物模型外推到人类，并预测各种结核感染区域的未结合浓度。我们发现，血浆游离药物 PK 并不总是结核感染组织未结合 PK 的良好替代物。
