As medicine shifts toward precision-based and personalized therapeutics, utilizing more complex biomolecules to treat increasingly difficult and rare conditions, microorganisms provide an avenue for realizing the production and processing necessary for novel drug pipelines. More so, probiotic microbes can be co-opted to deliver therapeutics by oral administration as living drugs, able to survive and safely transit the digestive tract. As living therapeutics are in their nascency, traditional pharmacokinetic–pharmacodynamic (PK–PD) models for evaluating drug candidates are not appropriate for this novel platform. Using a living therapeutic in late-stage clinical development for phenylketonuria (PKU) as a case study, we adapt traditional oral drug delivery models to properly evaluate and inform the engineering of living therapeutics. We develop the adapted for living therapeutics compartmental absorption and transit (ALT-CAT) model to provide metrics for drug efficacy across nine age groups of PKU patients and evaluate model parameters that are influenced by patient physiology, microbe selection and therapeutic production, and dosing formulations. In particular, the ALT-CAT model describes the mathematical framework to model the behavior of orally delivered engineered bacteria that act as living therapeutics by adapting similar methods that have been developed and widely-used for small molecular drug delivery and absorption.

中文翻译：

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使用肠道微生物进行代谢干预的定量模型

随着医学转向基于精确和个性化的治疗，利用更复杂的生物分子来治疗越来越困难和罕见的疾病，微生物为实现新型药物管道所需的生产和加工提供了途径。更重要的是，益生菌微生物可以通过口服给药作为活的药物来提供治疗，能够存活并安全地通过消化道。由于活体疗法尚处于起步阶段，用于评估候选药物的传统药代动力学-药效学 (PK-PD) 模型不适用于这一新平台。我们以苯丙酮尿症 (PKU) 后期临床开发中的活体疗法作为案例研究，采用传统的口服给药模型来正确评估活体疗法的工程并为其提供信息。我们开发一个适用于生活治疗学的吸收和转运( ALT - CAT ) 模型，以提供跨九个年龄组的PKU患者的药物疗效指标，并评估受患者生理、微生物选择和治疗产生影响的模型参数，和剂量配方。特别是，ALT-CAT 模型描述了模拟口服工程细菌行为的数学框架，这些工程细菌通过采用已开发并广泛用于小分子药物递送和吸收的类似方法来充当活疗法。