Uncovering the Impact of COVID-19 Mediated Bidirectional Dysregulation of CYP3A4 on Systemic and Pulmonary Drug Concentrations Using Physiologically Based Pharmacokinetic Modeling DOI Creative Commons
Chukwunonso K. Nwabufo

Drug Metabolism and Disposition, Journal Year: 2024, Volume and Issue: 53(1), P. 100008 - 100008

Published: Oct. 29, 2024

Several clinical studies have shown that COVID-19 increases the systemic concentration of drugs in hospitalized patients with COVID-19. However, it is unclear how COVID-19-mediated bidirectional dysregulation hepatic and pulmonary cytochrome P450 (CYP) 3A4 affects drug concentrations, especially lung tissue, which most affected by disease. Herein, physiologically based pharmacokinetic modeling was used to demonstrate differences concentrations 4 respiratory infectious disease when CYP3A4 concurrently downregulated liver upregulated on existing data COVID-19-CYP3A4 interactions at varying severity levels including outpatients, non-intensive care unit (ICU), ICU patients. The study showed metabolism primary determinant both despite concurrent CYP3A4. had exposure, a percentage increase area under concentration-time curve plasma compartment approximately 44%, 56%, 114%, 196% for clarithromycin, nirmatrelvir, dexamethasone, itraconazole, respectively, relative healthy group. Within cohort, clarithromycin exhibited its highest exposure tissue mass fold change 1189, whereas nirmatrelvir dexamethasone their compartment, changes about 126 5, compared maximum therapeutic target pathogens. Itraconazole significantly underexposed fluid potentially explaining limited efficacy treatment These findings underscore importance optimizing dosing regimens risk enhance safety profiles. SIGNIFICANCE STATEMENT: This investigated whether downregulation upregulation leads medicines. demonstrated intercompartmental were driven only expression. work suggests significant may be clinically relevant COVID-19-drug interactions, highlighting need this patient group improve efficacy.

Language: Английский

PBPK‐led assessment of antimalarial drugs as candidates for Covid‐19: Simulating concentrations at the site of action to inform repurposing strategies DOI Creative Commons
Nada Abla, Lisa M. Almond, Jennifer J. Bonner

et al.

Clinical and Translational Science, Journal Year: 2024, Volume and Issue: 17(7)

Published: July 1, 2024

Abstract The urgent need for safe, efficacious, and accessible drug treatments to treat coronavirus disease 2019 (COVID‐19) prompted a global effort evaluate repurposing opportunities. Pyronaridine amodiaquine are both components of approved antimalarials with in vitro activity against severe acute respiratory syndrome 2 (SARS‐CoV‐2). In does not always translate clinical efficacy across therapeutic dose range. This study applied available, verified, physiologically based pharmacokinetic (PBPK) models pyronaridine, amodiaquine, its active metabolite N‐desethylamodiaquine (DEAQ) predict concentrations lung tissue relative plasma or blood the default healthy virtual population. Lung exposures were compared published data reported range EC 50 values SARS‐CoV‐2. multicompartment permeability‐limited PBPK model, predicted total C max mass pyronaridine was 34.2 μM on Day 3, 30.5‐fold greater than (1.12 μM) 0.530 μM, 8.83‐fold (0.060 μM). perfusion‐limited DEAQ 3 (30.2 21.4‐fold (1.41 Based available data, DEAQ, but appeared sufficient inhibit SARS‐CoV‐2 replication. Simulations indicated standard dosing regimens pyronaridine‐artesunate artesunate‐amodiaquine have potential COVID‐19. These findings informed strategies select most relevant compounds investigation Clinical model verification may become from ongoing studies.

Language: Английский

Citations

2
Uncovering the Impact of COVID-19 Mediated Bidirectional Dysregulation of CYP3A4 on Systemic and Pulmonary Drug Concentrations Using Physiologically Based Pharmacokinetic Modeling DOI Creative Commons
Chukwunonso K. Nwabufo

Drug Metabolism and Disposition, Journal Year: 2024, Volume and Issue: 53(1), P. 100008 - 100008

Published: Oct. 29, 2024

Several clinical studies have shown that COVID-19 increases the systemic concentration of drugs in hospitalized patients with COVID-19. However, it is unclear how COVID-19-mediated bidirectional dysregulation hepatic and pulmonary cytochrome P450 (CYP) 3A4 affects drug concentrations, especially lung tissue, which most affected by disease. Herein, physiologically based pharmacokinetic modeling was used to demonstrate differences concentrations 4 respiratory infectious disease when CYP3A4 concurrently downregulated liver upregulated on existing data COVID-19-CYP3A4 interactions at varying severity levels including outpatients, non-intensive care unit (ICU), ICU patients. The study showed metabolism primary determinant both despite concurrent CYP3A4. had exposure, a percentage increase area under concentration-time curve plasma compartment approximately 44%, 56%, 114%, 196% for clarithromycin, nirmatrelvir, dexamethasone, itraconazole, respectively, relative healthy group. Within cohort, clarithromycin exhibited its highest exposure tissue mass fold change 1189, whereas nirmatrelvir dexamethasone their compartment, changes about 126 5, compared maximum therapeutic target pathogens. Itraconazole significantly underexposed fluid potentially explaining limited efficacy treatment These findings underscore importance optimizing dosing regimens risk enhance safety profiles. SIGNIFICANCE STATEMENT: This investigated whether downregulation upregulation leads medicines. demonstrated intercompartmental were driven only expression. work suggests significant may be clinically relevant COVID-19-drug interactions, highlighting need this patient group improve efficacy.

Language: Английский

Citations

0