(T-063) Pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation of a Novel, Directly Acting Antiviral, BDGR-251, in EEEV Infected Mice

Ashish Srivastava, PhD – Department of Pharmaceutical Sciences – University of Tennessee Health Science Center; Anjali Mishra, PhD – Regional Biocontainment Lab – University of Tennessee Health Science Center; Amarinder Singh, PhD – Department of Pharmaceutical Sciences – University of Tennessee Health Science Center; Jennifer Golden, PhD – Pharmaceutical Sciences Division, School of Pharmacy – University of Wisconsin- Madison, WI; Colleen Jonsson, PhD – Department of Microbiology Immunology and Biochemistry – University of Tennessee Health Science Center; Bernd Meibohm, PhD – Department of Pharmaceutical Sciences – University of Tennessee Health Science Center

BDGR-251 is a novel, directly acting antiviral with outstanding in vivo efficacy in both pre-exposure prophylaxis and post-exposure therapy in murine infection models of Eastern Equine Encephalitis Virus (EEEV). Here, we report the PKPD analysis of BDGR-251 in both therapeutic and prophylactic scenarios.

Drug plasma/brain concentrations and respective brain viral load (pfu) were compiled from three PKPD experiments (two prophylactic and one therapeutic) comprising different multiple dose regimens. In the first step, plasma concentrations were used to develop a population pharmacokinetic (PopPK) model using nonlinear mixed effects modeling (NONMEM). The second step comprised of estimating viral dynamic (VD) parameters by modeling the viral load data from control (no treatment) groups with tools like MATLAB-Simbiology and Microsoft Excel. In the final step, these two model components were combined into an integrated PKPD model in NONMEM.

Drug exposure in plasma and brain was found to be dose-proportional. The clearance and volume of distribution for BDGR-251 were found to be 0.494 L/h/kg and 2.17 L, respectively. Health status (infected vs. healthy) was identified as a covariate for bioavailability. The parameters related to viral growth dynamics were determined by fitting the standard Target Cell Limited viral dynamic model, including infected eclipse phase, as devised by Perelson et al., to the viral load vs time data for untreated control animals. The drug effect was modeled as a brain concentration-dependent suppression of viral replication. The resulting infectivity rate constant, beta, was found to be 7.0 x 10-10 with a virus production rate of 500 per hour and the fractional virus clearance rate of 0.2 per hour. In conclusion, we were able to develop a mechanistic PKPD model that can help us understand the drug concentration-dependent viral dynamics.

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Keywords: PKPD, Viral Dynamic, Target Cell Limited model, Exposure response, Antiviral