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

Antimicrobial Agents and Chemotherapy, Journal Year: 2024, Volume and Issue: 68(4)

Published: March 12, 2024

ABSTRACT Existing pharmacodynamic (PD) mathematical models for drug combinations discriminate antagonistic, additive, multiplicative, and synergistic effects, but fail to consider how concentration-dependent interaction effects may vary across an entire dose-response matrix. We developed a two-way (TWPD) model capture the PD of two-drug combinations. TWPD captures interactions between upstream downstream drugs that act on different stages viral replication, by quantifying efficacy parameters. applied previously published in vitro matrixes repurposed potential anti-Ebola anti-SARS-CoV-2 pairs. Depending pairing, recapitulated combined efficacies as or more accurately than existing can be used infer at untested concentrations. fits data slightly better one direction all pairs, meaning we tentatively drug. Based its high accuracy, could concert with PK estimate therapeutic pairs vivo .

Language: Английский

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Viral Rebound After Antiviral Treatment: A Mathematical Modeling Study of the Role of Antiviral Mechanism of Action

Interdisciplinary Sciences Computational Life Sciences, Journal Year: 2024, Volume and Issue: 16(4), P. 844 - 853

Published: July 21, 2024

Language: Английский

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Modeling the emergence of viral resistance for SARS-CoV-2 during treatment with an anti-spike monoclonal antibody

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 17, 2023

Abstract The COVID-19 pandemic has led to over 760 million cases and 6.9 deaths worldwide. To mitigate the loss of lives, emergency use authorization was given several anti-SARS-CoV-2 monoclonal antibody (mAb) therapies for treatment mild-to-moderate in patients with a high risk progressing severe disease. Monoclonal antibodies used treat SARS-CoV-2 target spike protein virus block its ability enter infect cells. therapy can thus accelerate decline viral load lower hospitalization rates among high-risk susceptible variants. However, resistance been observed, some leading transient rebound that be as large 3-4 orders magnitude. As mAbs represent proven choice other infections, evaluation treatment-emergent mAb help uncover underlying pathobiology infection may also development next generation therapies. Although expected, rebounds observed are much more difficult explain. We hypothesize replenishment cells is necessary generate rebound. Thus, we formulated two models different mechanisms cell (homeostatic proliferation return from an innate immune response anti-viral state) fit them data persons treated mAb. showed both explain emergence resistant associated rebounds. found variations supply rate adaptive immunity parameters have strong impact on magnitude or observability virus. Both why only individuals develop observable Our study highlights conditions lead subsequent treatments during acute infection. Author summary SARS-CoV-2. evolution variants compromised all currently authorized In one such antibody, bamlanivimab, nasal logs strains occur. better understand rebounds, developed incorporate drug sensitive well data. accurately capture dynamics proportion each studied individual little variation model parameters. best-fit parameters, bamlanivimab selects mutants expand levels due replenishment. ultimate clearance however depends immunity.

Language: Английский

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Exploring the treatment of SARS-CoV-2 with modified vesicular stomatitis virus

Journal of Theoretical Biology, Journal Year: 2024, Volume and Issue: unknown, P. 111959 - 111959

Published: Oct. 1, 2024

Language: Английский

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