Hybrid physiologically-based pharmacokinetic model for remdesivir: Application to SARS-CoV-2.
Clin Transl Sci
; 14(3): 1082-1091, 2021 05.
Article
in English
| MEDLINE | ID: covidwho-1010762
ABSTRACT
A novel coronavirus, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) or coronavirus disease 2019 (COVID-19), has caused a pandemic that continues to cause catastrophic health and economic carnage and has escalated the identification and development of antiviral agents. Remdesivir (RDV), a prodrug and requires intracellular conversions to the active triphosphate nucleoside (TN) has surfaced as an active anti-SARS-CoV-2 drug. To properly design therapeutic treatment regimens, it is imperative to determine if adequate intracellular TN concentrations are achieved in target tissues, such as the lungs. Because measurement of such concentrations is unrealistic in patients, a physiologically-based pharmacokinetic (PBPK) model was developed to characterize RDV and TN disposition. Specifically, a hybrid PBPK model was developed based on previously reported data in humans. The model represented each tissue as a two-compartment model-both extracellular and intracellular compartment wherein each intracellular compartment contained a comprehensive metabolic model to the ultimate active metabolite TN. Global sensitivity analyses and Monte-Carlo simulations were conducted to assess which parameters and how highly sensitive ones impacted peripheral blood mononuclear cells and intracellular lung TN profiles. Finally, clinical multiple-dose regimens indicated that minimum lung intracellular TN concentrations ranged from ~ 9 uM to 4 uM, which suggest current regimens are effective based on in vitro half-maximal effective concentration values. The model can be used to explore tissue drug disposition under various conditions and regimens, and expanded to pharmacodynamic models.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Adenosine Monophosphate
/
Alanine
/
SARS-CoV-2
/
COVID-19 Drug Treatment
Type of study:
Prognostic study
Limits:
Humans
Language:
English
Journal:
Clin Transl Sci
Year:
2021
Document Type:
Article
Affiliation country:
Cts.12975
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