A quantitative model for metabolic intervention using gut microbes

Abstract

5As medicine shifts toward precision-based and personalized therapeutics, utilizing more complex biomolecules to 6 treat increasingly difficult and rare conditions, microorganisms provide an avenue for realizing the production and 7 processing necessary for novel drug pipelines. More so, probiotic microbes can be co-opted to deliver therapeutics 8 by oral administration as living drugs, able to survive and safely transit the digestive tract. As living therapeutics are 9 in their nascency, traditional pharmacokinetic-pharmacodynamic (PK-PD) models for evaluating drug candidates 10 are not appropriate for this novel platform. Using a living therapeutic in late-stage clinical development for 11 phenylketonuria (PKU) as a case study, we adapt traditional oral drug delivery models to properly evaluate and 12 inform the engineering of living therapeutics. We develop the adapted for living therapeutics compartmental 13 absorption and transit (ALT-CAT) model to provide metrics for drug efficacy across nine age groups of PKU patients 14 and evaluate model parameters that are influenced by patient physiology, microbe selection and therapeutic 15 production, and dosing formulations. 16 Importance 17This work describes a kinetic model to study the behavior of orally delivered living therapeutics. Such therapeutics 18 are becoming increasingly relevant and are an exciting mode of drug delivery that stems from the growing interest 19 through the convergence of advances in synthetic biology of probiotics and gut microbes as well as microbiome 20 science. In particular, this work describes the development of a mathematical framework (pharmacokinetic-21 pharmacodynamic, PK-PD) called ALT-CAT to model the behavior of orally delivered engineered bacteria that act as 22 living therapeutics by adapting similar methods that have been developed and widely-used for small molecular drug 23 delivery and absorption. 24 2 Introduction 25The most common and practical route of drug delivery is oral ingestion, pairing patient convenience and high 26 compliance with ease of administration and stability. While a simple initial assessment of a drug's biochemical 27 feasibility for oral delivery can be predicted using the biopharmaceutical classification system (BCS) (1) or rule of 28 five (Ro5) (2), these evaluations do not inform the further complexities of selecting lead candidates, developing a 29 dosage or release strategy, effective bioavailability, and pharmacokinetics. Accordingly, a range of models -in vitro 30(3) and in vivo (4), static (5) and dynamic (6, 7), molecular (8) and system environment (9) -are used extensively in 31 drug development to evaluate and hone desired features. 32 33 An economically appealing alternative, trading human capital and consumables for computational resources (time 34 and power), is the modeling of drug absorption in the gastrointestinal tract (GIT). In silico models have been 35 developed for both molecular interactions (10), such as receptor binding or transport, and physiology-based 36 pharmacokinetics...