Two-way pharmacodynamic modeling of drug combinations and its application to pairs of repurposed Ebola and SARS-CoV-2 agents
Existing pharmacodynamic (PD) mathematical models for drug combinations 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 downstream 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:68 |
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| Enthalten in: |
Antimicrobial agents and chemotherapy - 68(2024), 4 vom: 03. Apr., Seite e0101523 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Xu, Shuang [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 04.04.2024 Date Revised 05.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1128/aac.01015-23 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM369598474 |
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| 520 | |a Existing pharmacodynamic (PD) mathematical models for drug combinations 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 downstream 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 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a drug repurposing | |
| 650 | 4 | |a two-way pharmacodynamic modeling | |
| 650 | 4 | |a upstream drug-dependent pharmacodynamic parameters | |
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| 700 | 1 | |a Goyal, Ashish |e verfasserin |4 aut | |
| 700 | 1 | |a White, Judith M |e verfasserin |4 aut | |
| 700 | 1 | |a Polyak, Stephen J |e verfasserin |4 aut | |
| 700 | 1 | |a Schiffer, Joshua T |e verfasserin |4 aut | |
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