Physiologically Based Pharmacokinetic Modeling Approaches for Patients With SARS-CoV-2 Infection: A Case Study With Imatinib.
J Clin Pharmacol
; 62(10): 1285-1296, 2022 10.
Article
in English
| MEDLINE | ID: covidwho-1802328
ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which causes coronavirus disease 2019 (COVID-19), manifests as mild respiratory symptoms to severe respiratory failure and is associated with inflammation and other physiological changes. Of note, substantial increases in plasma concentrations of α1 -acid-glycoprotein and interleukin-6 have been observed among patients admitted to the hospital with advanced SARS-CoV-2 infection. A physiologically based pharmacokinetic (PBPK) approach is a useful tool to evaluate and predict disease-related changes on drug pharmacokinetics. A PBPK model of imatinib has previously been developed and verified in healthy people and patients with cancer. In this study, the PBPK model of imatinib was successfully extrapolated to patients with SARS-CoV-2 infection by accounting for disease-related changes in plasma α1 -acid-glycoprotein concentrations and the potential drug interaction between imatinib and dexamethasone. The model demonstrated a good predictive performance in describing total and unbound imatinib concentrations in patients with SARS-CoV-2 infection. PBPK simulations highlight that an equivalent dose of imatinib may lead to substantially higher total drug concentrations in patients with SARS-CoV-2 infection compared to that in patients with cancer, while the unbound concentrations remain comparable between the 2 patient populations. This supports the notion that unbound trough concentration is a better exposure metric for dose adjustment of imatinib in patients with SARS-CoV-2 infection, compared to the corresponding total drug concentration. Potential strategies for refinement and generalization of the PBPK modeling approach in the patient population with SARS-CoV-2 are also provided in this article, which could be used to guide study design and inform dose adjustment in the future.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Imatinib Mesylate
/
COVID-19 Drug Treatment
Type of study:
Case report
/
Experimental Studies
/
Prognostic study
Limits:
Humans
Language:
English
Journal:
J Clin Pharmacol
Year:
2022
Document Type:
Article
Affiliation country:
Jcph.2065
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