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Two-way pharmacodynamic modeling of drug combinations and its application to pairs of repurposed Ebola and SARS-CoV-2 agents

Xu et al., Antimicrobial Agents and Chemotherapy, doi:10.1128/aac.01015-23
Apr 2024  
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In Silico study supporting the synergistic combination of nitazoxanide and remdesivir for SARS-CoV-2. Authors developed a two-way pharmacodynamic modeling approach to capture the concentration-dependent drug-drug interactions and combined efficacy of nitazoxanide and remdesivir using previously published In Vitro dose-response data.
4 preclinical studies support the efficacy of nitazoxanide for COVID-19:
1 In Silico study Xu
2 In Vitro studies Miorin, Riccio
1 In Vivo animal study Miorin
Study covers nitazoxanide and remdesivir.
Xu et al., 3 Apr 2024, USA, peer-reviewed, 7 authors. Contact: jschiffe@fredhutch.org.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
This PaperNitazoxanideAll
Two-way pharmacodynamic modeling of drug combinations and its application to pairs of repurposed Ebola and SARS-CoV-2 agents
Shuang Xu, Shadisadat Esmaeili, E Fabian Cardozo-Ojeda, Ashish Goyal, Judith M White, Stephen J Polyak, Joshua T Schiffer
Antimicrobial Agents and Chemotherapy, doi:10.1128/aac.01015-23
Existing pharmacodynamic (PD) mathematical models for drug combina tions discriminate antagonistic, additive, multiplicative, and synergistic effects, but fail to consider how concentration-dependent drug interaction effects may vary across an entire dose-response matrix. We developed a two-way pharmacodynamic (TWPD) model to capture the PD of two-drug combinations. TWPD captures interactions between upstream and downstream drugs that act on different stages of viral replication, by quantifying upstream drug efficacy and concentration-dependent effects on down stream drug pharmacodynamic parameters. We applied TWPD to previously published in vitro drug matrixes for repurposed potential anti-Ebola and anti-SARS-CoV-2 drug pairs. Depending on the drug pairing, the model recapitulated combined efficacies as or more accurately than existing models and can be used to infer efficacy at untested drug concentrations. TWPD fits the data slightly better in one direction for all drug pairs, meaning that we can tentatively infer the upstream drug. Based on its high accuracy, TWPD could be used in concert with PK models to estimate the therapeutic effects of drug pairs in vivo.
AUTHOR CONTRIBUTIONS Shuang ADDITIONAL FILES The following material is available online. Supplemental Material Supplemental material (AAC01015-23-s0001.docx). Figures S1 to S7; Tables S1 to S10 .
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