INTRODUCTION Acute intermittent porphyria (AIP) is characterized by hepatic over-production of the heme precursors when aminolevulinic acid (ALA)-synthase 1 is induced by endogenous or environmental factors. The aim of this study was to develop a semi-mechanistic computational model to characterize urine accumulation of heme precursors during acute attacks based on experimental pharmacodynamics data and support the development of new therapeutic strategies. METHODS Male AIP mice received recurrent phenobarbital challenge starting on days 1, 9, 16 and 30. 24-h urine excretion of ALA, porphobilinogen (PBG) and porphyrins from challenges D1, D9 and D30 constituted the training data set to build the mechanistic model using the population approach. In a second study, porphyrin and porphyrin precursor excretion from challenge D16 were used as a validation data set. RESULTS The computational model presented the following features: (i) urinary excretion of ALA, PBG and porphyrins was governed by unmeasured circulating heme precursor amounts, (ii) the circulating amounts of ALA and PBG were the precursors of circulating amounts of PBG and porphyrins, respectively, and (iii) the phenobarbital effect linearly increased the synthesis of circulating ALA and PBG levels. The model displayed good parameter precision (coefficient of variation below 32% in all parameters), and adequately described the experimental data. Finally, a theoretical hemin effect was implemented to illustrate the applicability of the model to dosage optimization in drug therapies. CONCLUSIONS A semi-mechanistic disease model was successfully developed to describe the temporal evolution of urinary heme precursor excretion during recurrent biochemical-induced acute attacks in AIP mice. This model represents the first computational approach to explore and optimize current and new therapies.

中文翻译：

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在急性间歇性卟啉症小鼠模型中苯巴比妥诱发的急性发作的计算疾病模型。

简介急性间歇性卟啉症（AIP）的特征是当内源性或环境因素诱导氨基乙酰丙酸（ALA）合成酶1时，肝血红素前体的过量生产。这项研究的目的是基于实验药效学数据，开发一种半机械计算模型来表征急性发作期间血红素前体的尿液蓄积，并支持新治疗策略的发展。方法雄性AIP小鼠在第1、9、16和30天开始接受苯巴比妥反复发作。来自D1，D9和D30攻击的24小时尿液中ALA，胆色素原（PBG）和卟啉的排泄构成了建立机械模型的训练数据集使用人口方法。在第二项研究中 挑战D16中的卟啉和卟啉前体排泄物用作验证数据集。结果计算模型具有以下特点：（i）尿中排泄的ALA，PBG和卟啉受不可测的循环血红素前体量控制；（ii）ALA和PBG的循环量是PBG和卟啉的循环量的前体， （iii）苯巴比妥效应线性增加循环ALA和PBG水平的合成。该模型显示出良好的参数精度（所有参数的变异系数均低于32％），并充分描述了实验数据。最后，通过理论上的血红素效应来说明该模型在药物治疗中优化剂量的适用性。结论成功开发了一种半机械疾病模型来描述AIP小鼠在反复生化诱导的急性发作过程中尿血红素前体排泄的时间演变。该模型代表了探索和优化当前和新疗法的第一种计算方法。