Preclinical and Translational Sciences
James Gosset (he/him/his)
Associate Research Fellow
Pfizer Inc
Cambridge, Massachusetts
Fei Hua, PhD
VP of Modeling and Simulation Services
Applied BioMath
Concord
DMPK-on-a-Chip: Developing an Organ-Linked Microphysiological System to Inform Human Pharmacokinetics
In early drug design, there are significant efforts towards characterization of the ADME (absorption, distribution, metabolism, and excretion) properties of potential drug candidates using both in vitro and preclinical in vivo systems. We use these data to predict human pharmacokinetics (PK) and drug-drug interactions (DDI) enabling the selection of drug candidates for clinical development in human.
Over recent years, substantial investment of government and venture capital funding have produced novel technologies of more intact systems that can represent human organ physiology. These include cell culture systems that go beyond single cell type monolayer cultures (e.g., organoids, co-cultures in 2D and 3D formats) and human tissue chips, aka microphysiological systems (MPS) can replicate several organ systems (e.g., liver, gut, kidney).
While human MPS chips are primarily used in basic research, such technologies have limited utility in pharmacokinetic applications because the flow-through fluidic design, chip material, and small media / tissue volumes do not support drug quantification.
For this unmet need, in partnership with Javelin Biotech we designed single- and multi-tissue chips for pharmacokinetics applications. These chips are recirculating milli-fluidic chips made of low non-specific binding thermoplastic material. The milli-fluidic chips accommodate larger tissue and media than microfluidic chips to enable multiple media sampling for kinetic data. The recirculatory perfusion system dramatically extends drug-tissue retention time allowing low-clearance and low-permeability drug studies. We characterized each tissue (liver, kidney (proximal tubule) and skeletal muscle) functionality for 21+ days with single- and multi-tissue chips and demonstrated physiologically relevant levels of enzyme and transporter activity in order to conduct pharmacokinetic studies.
A diverse set of small molecule drugs from all extended clearance classification system (ECCS) classes with various clearance mechanisms was evaluated on single- and multi-tissue chips. We quantified on-chip pharmacokinetic parameters, such as hepatic metabolism, uptake and disposition, tubular secretion and reabsorption, and muscle disposition. These on-chip pharmacokinetic parameters were then successfully scaled to clinical parameters for IV drugs: hepatic clearance, renal clearance, and volume of distribution. The predicted PK parameters showed high correlation to clinical parameters.
The vision is to employ this platform in the early development of drug discovery, where dramatic reduction in the required API, offer an alternative to, and hopefully a replacement of, pharmacokinetic studies in laboratory animals for the purposes of understanding drug disposition in an intact mammal as a surrogate for human.