A Systems Pharmacology approach to predict the effects of pregnancy and infectious diseases on transporter-mediated drug disposition

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SUMMARY Pregnancy and inflammation (due to infectious diseases) are each known to alter drug pharmacokinetics (PK) by changing the expression and activity of transporters and/or drug-metabolizing enzymes (e.g. CYPs). Quantifying changes in drug PK caused by pregnancy and/or cytokines (elevated during inflammation) is important for rational design of dosing regimens of drugs for pregnant women with infectious diseases. While changes in the PK of CYP-cleared drugs by pregnancy and cytokines have been well-delineated, such data are sorely missing for transporters. However, obtaining the latter for every possible transported drug administered to pregnant women (with or without infection) is logistically impossible. Therefore, alternative approaches that can generalize across drugs, transporters and pro-inflammatory infectious diseases are urgently needed. These approaches should accurately predict the alteration in in vivo activity of transporters by pregnancy and pro-inflammatory cytokines. In this proposal, we propose a systems pharmacology approach to predict the effects of pregnancy and/or pro-inflammatory infectious diseases on transporter-mediated drug PK. Our hypothesis is that the magnitude of change in drug PK by pregnancy and/or cytokines can be predicted through clinical PK studies using probe drugs and in vitro experimental data as well as Physiologically Based Pharmacokinetic (PBPK) modeling and simulation (M&S). Transporter probe drugs, unlike CYP probe drugs, have the limitations that they are not selective. To overcome this limitation, we propose a two-pronged approach which utilizes both primary human cells (hepatocytes, renal epithelial cells, and intestinal enterocytes) and transfected cells expressing individual transporters of interest. Using quantitative targeted proteomics, the human cells will allow us to determine the effects of pregnancy hormones or cytokines on the expression of transporters in these cells. The transporter-transfected cell studies will allow us to determine the intrinsic transport clearance of a drug by a single transporter per pmol of a transporter. Then, the in vitro intrinsic transporter-mediated clearances in primary cells will be extrapolated to in vivo using PBPK M&S. Combined, these data will allow us to predict transporter-mediated clearance of drugs in pregnant women with and without infection. These studies will address a critical gap in our understanding of the effects of pregnancy and/or pro-inflammatory infectious diseases on transporter- mediated drug disposition. Since our approach can be applied to other drugs and other inflammatory diseases throughout pregnancy, its significance goes well beyond the drugs and inflammatory diseases investigated here. We would like this application to be considered under the NIH-FAPESP initiative (NOT-TW-16-001). We are requesting support for only the in vitro studies proposed here as well as PBPK M&S. FAPESP will support the clinical PK studies in pregnant women with infectious diseases in Brazil. The clinical PK data obtained in Brazil will be used to verify our PBPK model predictions.