tetano
Editor, Senior Moderator
Clin Transl Sci
. 2021 Jan 6.
doi: 10.1111/cts.12975. Online ahead of print.
Hybrid physiologically-based pharmacokinetic model for remdesivir: Application to SARS-CoV-2
James M Gallo[SUP] 1 [/SUP]
Affiliations
Abstract
A novel coronavirus, SARS-CoV-2 or 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 lung. Since measurement of such concentrations is unrealistic in patients, a physiologically-based pharmacokinetic model (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 2-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 (PMNCs) and intracellular lung TN profiles. Finally, clinical multiple-dose regimens indicated that minimum lung intracellular TN concentrations ranged from approximately 9 uM to 4 uM, which suggest current regimens are effective based on in vitro EC50 values. The model can be used to explore tissue drug disposition under various conditions and regimens, and expanded to pharmacodynamic models.
. 2021 Jan 6.
doi: 10.1111/cts.12975. Online ahead of print.
Hybrid physiologically-based pharmacokinetic model for remdesivir: Application to SARS-CoV-2
James M Gallo[SUP] 1 [/SUP]
Affiliations
- PMID: 33404204
- DOI: 10.1111/cts.12975
Abstract
A novel coronavirus, SARS-CoV-2 or 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 lung. Since measurement of such concentrations is unrealistic in patients, a physiologically-based pharmacokinetic model (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 2-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 (PMNCs) and intracellular lung TN profiles. Finally, clinical multiple-dose regimens indicated that minimum lung intracellular TN concentrations ranged from approximately 9 uM to 4 uM, which suggest current regimens are effective based on in vitro EC50 values. The model can be used to explore tissue drug disposition under various conditions and regimens, and expanded to pharmacodynamic models.