PBPK-led assessment of antimalarial drugs as candidates for Covid-19: Simulating concentrations at the site of action to inform repurposing strategies.
Clin Transl Sci
; 17(7): e13865, 2024 Jul.
Article
de En
| MEDLINE
| ID: mdl-39020517
ABSTRACT
The urgent need for safe, efficacious, and accessible drug treatments to treat coronavirus disease 2019 (COVID-19) prompted a global effort to evaluate drug repurposing opportunities. Pyronaridine and amodiaquine are both components of approved antimalarials with in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In vitro activity does not always translate to clinical efficacy across a therapeutic dose range. This study applied available, verified, physiologically based pharmacokinetic (PBPK) models for pyronaridine, amodiaquine, and its active metabolite N-desethylamodiaquine (DEAQ) to predict drug concentrations in lung tissue relative to plasma or blood in the default healthy virtual population. Lung exposures were compared to published data across the reported range of in vitro EC50 values against SARS-CoV-2. In the multicompartment permeability-limited PBPK model, the predicted total Cmax in lung mass for pyronaridine was 34.2 µM on Day 3, 30.5-fold greater than in blood (1.12 µM) and for amodiaquine was 0.530 µM, 8.83-fold greater than in plasma (0.060 µM). In the perfusion-limited PBPK model, the DEAQ predicted total Cmax on Day 3 in lung mass (30.2 µM) was 21.4-fold greater than for plasma (1.41 µM). Based on the available in vitro data, predicted drug concentrations in lung tissue for pyronaridine and DEAQ, but not amodiaquine, appeared sufficient to inhibit SARS-CoV-2 replication. Simulations indicated standard dosing regimens of pyronaridine-artesunate and artesunate-amodiaquine have potential to treat COVID-19. These findings informed repurposing strategies to select the most relevant compounds for clinical investigation in COVID-19. Clinical data for model verification may become available from ongoing clinical studies.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Repositionnement des médicaments
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SARS-CoV-2
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Traitements médicamenteux de la COVID-19
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Amodiaquine
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Poumon
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Antipaludiques
Limites:
Humans
Langue:
En
Journal:
Clin Transl Sci
Année:
2024
Type de document:
Article
Pays d'affiliation:
Suisse
Pays de publication:
EEUU
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ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA