Integrated Gut and Liver Microphysiological Systems for Quantitative In Vitro Pharmacokinetic Studies

Investigation of the pharmacokinetics (PK) of a compound is of significant importance during the early stages of drug development, and therefore several in vitro systems are routinely employed for this purpose. However, the need for more physiologically realistic in vitro models has recently fueled the emerging field of tissue-engineered 3D cultures, also referred to as organs-on-chips, or microphysiological systems (MPSs). We have developed a novel fluidic platform that interconnects multiple MPSs, allowing PK studies in multi-organ in vitro systems along with the collection of high-content quantitative data. This platform was employed here to integrate a gut and a liver MPS together in continuous communication, and investigate simultaneously different PK processes taking place after oral drug administration in humans (e.g., intestinal permeability, hepatic metabolism). Measurement of tissue-specific phenotypic metrics indicated that gut and liver MPSs can be fluidically coupled with circulating common medium without compromising their functionality. The PK of diclofenac and hydrocortisone was investigated under different experimental perturbations, and results illustrate the robustness of this integrated system for quantitative PK studies. Mechanistic model-based analysis of the obtained data allowed the derivation of the intrinsic parameters (e.g., permeability, metabolic clearance) associated with the PK processes taking place in each MPS. Although these processes were not substantially affected by the gut-liver interaction, our results indicate that inter-MPS communication can have a modulating effect (hepatic metabolism upregulation). We envision that our integrative approach, which combines multi-cellular tissue models, multi-MPS platforms, and quantitative mechanistic modeling, will have broad applicability in pre-clinical drug development.United States. Defense Advanced Research Projects Agency (Grant W911NF-12-2- 0039)National Institutes of Health (U.S.) (Grant 4-UH3-TR000496-0

Population variability in animal health: Influence on dose-exposure-response relationships: Part II: Modelling and simulation

During the 2017 Biennial meeting, the American Academy of Veterinary Pharmacology and Therapeutics hosted a 1‐day session on the influence of population variability on dose‐exposure‐response relationships. In Part I, we highlighted some of the sources of population variability. Part II provides a summary of discussions on modelling and simulation tools that utilize existing pharmacokinetic data, can integrate drug physicochemical characteristics with species physiological characteristics and dosing information or that combine observed with predicted and in vitro information to explore and describe sources of variability that may influence the safe and effective use of veterinary pharmaceuticals

Why has model-informed precision dosing not yet become common clinical reality?:Lessons from the past and a roadmap for the future

Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or lowering the risk of toxicity. Model-informed precision dosing (MIPD) may improve treatment outcomes by achieving the optimal dose for an individual patient. There is, however, relatively little published evidence of large-scale utility and impact of MIPD, where it is often implemented as local collaborative efforts between academia and healthcare. This article highlights some successful applications of bringing MIPD to clinical care and proposes strategies for wider integration in healthcare. Considerations are brought up herein that will need addressing to see MIPD become "widespread clinical practice," among those, wider interdisciplinary collaborations and the necessity for further evidence-based efficacy and cost-benefit analysis of MIPD in healthcare. The implications of MIPD on regulatory policies and pharmaceutical development are also discussed as part of the roadmap

Interconnected Microphysiological Systems for Quantitative Biology and Pharmacology Studies

Microphysiological systems (MPSs) are in vitro models that capture facets of in vivo organ function through use of specialized culture microenvironments, including 3D matrices and microperfusion. Here, we report an approach to co-culture multiple different MPSs linked together physiologically on re-useable, open-system microfluidic platforms that are compatible with the quantitative study of a range of compounds, including lipophilic drugs. We describe three different platform designs - "4-way", "7-way", and "10-way" - each accommodating a mixing chamber and up to 4, 7, or 10 MPSs. Platforms accommodate multiple different MPS flow configurations, each with internal re-circulation to enhance molecular exchange, and feature on-board pneumatically-driven pumps with independently programmable flow rates to provide precise control over both intra- and inter-MPS flow partitioning and drug distribution. We first developed a 4-MPS system, showing accurate prediction of secreted liver protein distribution and 2-week maintenance of phenotypic markers. We then developed 7-MPS and 10-MPS platforms, demonstrating reliable, robust operation and maintenance of MPS phenotypic function for 3 weeks (7-way) and 4 weeks (10-way) of continuous interaction, as well as PK analysis of diclofenac metabolism. This study illustrates several generalizable design and operational principles for implementing multi-MPS "physiome-on-a-chip" approaches in drug discovery.United States. Army Research Office (Grant W911NF-12-2-0039

Biopharmaceutical considerations in paediatrics with a view to the evaluation of orally administered drug products – a PEARRL review.

Objectives: In this review, the current biopharmaceutical approaches for evaluation of oral formulation performance in paediatrics are discussed. Key findings: The paediatric gastrointestinal (GI) tract undergoes numerous morphological and physiological changes throughout its development and growth. Some physiological parameters are yet to be investigated, limiting the use of the existing in vitro biopharmaceutical tools to predict the in vivo performance of paediatric formulations. Meals and frequencies of their administration evolve during childhood and affect oral drug absorption. Furthermore, the establishment of a paediatric Biopharmaceutics Classification System (pBCS), based on the adult Biopharmaceutics Classification System (BCS), requires criteria adjustments. The usefulness of computational simulation and modeling for extrapolation of adult data to paediatrics has been confirmed as a tool for predicting drug formulation performance. Despite the great number of successful physiologically based pharmacokinetic models to simulate drug disposition, the simulation of drug absorption from the GI tract is a complicating issue in paediatric populations. Summary: The biopharmaceutics tools for investigation of oral drug absorption in paediatrics need further development, refinement and validation. A combination of in vitro and in silico methods could compensate for the uncertainties accompanying each method on its own

Parsing interindividual drug variability: an emerging role for systems pharmacology

There is notable interindividual heterogeneity in drug response, affecting both drug efficacy and toxicity, resulting in patient harm and the inefficient utilization of limited healthcare resources. Pharmacogenomics is at the forefront of research to understand interindividual drug response variability, but although many genotype-drug response associations have been identified, translation of pharmacogenomic associations into clinical practice has been hampered by inconsistent findings and inadequate predictive values. These limitations are in part due to the complex interplay between drug-specific, human body and environmental factors influencing drug response and therefore pharmacogenomics, whilst intrinsically necessary, is by itself unlikely to adequately parse drug variability. The emergent, interdisciplinary and rapidly developing field of systems pharmacology, which incorporates but goes beyond pharmacogenomics, holds significant potential to further parse interindividual drug variability. Systems pharmacology broadly encompasses two distinct research efforts, pharmacologically-orientated systems biology and pharmacometrics. Pharmacologically-orientated systems biology utilizes high throughput omics technologies, including next-generation sequencing, transcriptomics and proteomics, to identify factors associated with differential drug response within the different levels of biological organization in the hierarchical human body. Increasingly complex pharmacometric models are being developed that quantitatively integrate factors associated with drug response. Although distinct, these research areas complement one another and continual development can be facilitated by iterating between dynamic experimental and computational findings. Ultimately, quantitative data-derived models of sufficient detail will be required to help realize the goal of precision medicine. WIREs Syst Biol Med 2015, 7:221–241. doi: 10.1002/wsbm.130