P137 Quantitative pharmacology studies in microphysiological systems (MPS)

Murat Cirit , MIT, Cambridge, MA
In vitro models have been developed and utilized in various stages for the preclinical development. Compared to animal models, in vitro models have advantages such as high-throughput capability, low cost, well-controlled experimental parameters and fewer ethical concerns etc. However, the simplicity of the conventional in vitro models makes them incapable of achieving adequate physiological relevance for mimicking the human body, which is a dynamic system that has complex three-dimensional microenvironment, intracellular communications and organ interactions. Hence, there is an urgent need to develop more physiologically relevant in vitro systems for better simulating the human body in response of drugs and providing more reliable in-vitro in-vivo translation (IVIVT) from preclinical results to clinical outcomes.

Our integrative approach merges quantitative systems pharmacology with MPS systems to provide an improved approach for predictive preclinical drug discovery. Acceptance of these emerging technologies by the pharmaceutical industries will require quantitative characterization of MPSs and mechanistic analysis of experimental findings sufficient to translate resulting insights from in vitro to in vivo. Thus, we describe a systems pharmacology perspective on this problem, incorporating more mechanistic detail for tissue chip studies than traditional pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) models yet within broadly comprehensive scope. These systems pharmacology approaches offer new insight into design of experiments, data interpretation and organ-specific responses, which can be translated to in vivo responses, such as patient-to-patient variability, drug efficacy and toxicity.

Our studies include pharmacokinetics and safety pharmacology using individual MPS or integrated MPSs (up to different 10-MPS). We investigated the effects of donor variability on pharmacokinetics in the liver-on-a-chip technology with 5 different hepatocytes donors and 6 different drugs (diclofenac, lidocaine, ibuprofen, phenacetin, predsinolone and propranolol) and successfully predicted patient variability in phase 1 clinical trials of lidocaine (Tsamandouras N et al, JPET, 2017). We also studied the effects of MPS-MPS crosstalk on pharmacokinetic parameters in multi-MPS systems. Our findings show that interconnecting gut and liver MPSs has a differential effect on liver MPS Cytochrome P450 functions (Chen WLK et al, 2017, Bioengineering and Biotechnology & Tsamandouras et al, 2017, AAPSJ, accepted). These studies are also expanded for higher degree multi-MPS systems, such as 4-MPS, 7-MPS and 10-MPS platforms (Cirit M et al, in preparation). Our safety pharmacology applications also includes individual and multi-MPS technologies focusing on hepatotoxic drugs (tolcapone, diclofenac, celecoxib), cardiotoxic drugs (doxorubucin), nephrotoxic drugs/compunds (cisplatin, gentamicin, cadmium, rifampicin), and neurotoxic drugs (docetaxel, vincristine and bortezomib).