A PKPD model of ribavirin in Lassa virus infected mice
Christine J. Kleist (1), Lisa Oestereich (2), Stephan Günther (2), Sebastian G. Wicha (1)
(1) Dept. of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Germany, (2) Dept. of Virology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
Objectives: Ribavirin is a broad-spectrum antiviral, which is used in the therapy of the Lassa fever. In vitro ribavirin showed inhibitory effects against the replication of the Lassa virus, but in vivo this effect was minor. Nevertheless, ribavirin improved the clinical outcome, especially in combination with the strong antiviral favipiravir [1]. Carrillo-Bustamante et al. investigated different mechanisms of action of ribavirin against the Lassa virus and identified no direct antiviral effect, but a relation between dose and aspartate aminotransferase (AST) release from damaged cells suggesting some cell-protective effects of ribavirin [2]. Yet, no PK was considered in [2] and solely an ED50 was estimated. The aim of this project was to link a literature-based PK model to the PD data from [1], i.e. to develop a PKPD model for ribavirin in mice, in order to determine an in vivo EC50 of ribavirin effects in Lassa infected mice.
Methods: We combined the PD model with the most likely mechanism of action (model C), of Carrillo-Bustamante et al. [2] with the PK model for ribavirin in mice of Endres et al. [3]. Model C describes the cell protective effect of ribavirin by reducing the death rate of the infected cells. The estimates of the PK model were fixed to the pharmacokinetic parameters for Ent1(+/+) (wildtype for equilibrative nucleoside transporter 1) mice referring to the values described in the literature [3], as no ribavirin plasma concentrations of mice were available to us from the infected mice [1].
The values of the initial target cell inoculum, the initial virus inoculum, the clearance of the free virus and of the AST molecules were fixed to the literature values, as in the original PD model [2]. The other PD parameters (basic reproductive number R0, death rate of infected cells δI, viral production rate p, factor α describing AST release from dying infected cells, constant source for AST sx) were re-evaluated in the PKPD model. Model selection was guided by graphical criteria, i.e. goodness of fit plots and visual predictive checks and the difference in the objective function value.
Results: First, the EC50 was estimated with all other estimates fixed to the literature values. Goodness of fit plots and VPC showed a good model fit for the viral load, but not for the AST concentrations. In the next step all AST related parameters were estimated, while parameters related to viral load remained fixed. The model fit increased substantially guided by a drop of the objective function value of -38.162. For the final PKPD model the estimated EC50 for ribavirin was 0.0409 µg/mL. Further estimates of the model were α = 0.00141 (literature: 0.0018), sx = 79.8 U/L (literature: 66.8 U/L), R0, δI and p remained fixed to the literature values [2].
Conclusion: Using the developed PKPD model, we could successfully estimate an in vivo EC50 for the cell protective effects of ribavirin against Lassa fever. In a next step, changing the PK model for mice into a human PK model, will give us the option to simulate the effect of ribavirin in humans and validate the model against clinical data.
[1] Oestereich L, Rieger T, Lüdtke A, et al (2016) Efficacy of Favipiravir Alone and in Combination With Ribavirin in a Lethal, Immunocompetent Mouse Model of Lassa Fever. J Infect Dis 213:934–938. https://doi.org/10.1093/infdis/jiv522
[2] Carrillo-Bustamante P, Nguyen THT, Oestereich L, et al (2017) Determining Ribavirin’s mechanism of action against Lassa virus infection. Sci Rep 7:11693. https://doi.org/10.1038/s41598-017-10198-0
[3] Endres CJ, Moss AM, Govindarajan R, et al (2009) The role of nucleoside transporters in the erythrocyte disposition and oral absorption of ribavirin in the wild-type and equilibrative nucleoside transporter 1(-/-) mice. J Pharmacol Exp Ther 331:287–296. https://doi.org/10.1124/jpet.109.153130
