Disease–Drug–Drug Interaction of Imatinib in COVID‐19 ARDS: A Pooled Population Pharmacokinetic Analysis

Disease–Drug–Drug Interaction of Imatinib in COVID‐19 ARDS: A Pooled Population Pharmacokinetic Analysis

ABSTRACT Prior pharmacokinetic (PK) analysis revealed that increased alpha‐1‐acid glycoprotein (AAG) levels are associated with decreased imatinib unbound fraction in coronavirus disease 2019 (COVID‐19) patients. This study aimed to investigate the PK of total and unbound concentrations of imatinib...

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Main Authors: Medhat M. Said, Job R. Schippers, Leila Atmowihardjo, Yingxue Li, Mick S. van derPlas, Harm J. Bogaard, Lieuwe D. J. Bos, Ron A. A. Mathôt, Jurjan Aman, Eleonora L. Swart, Imke H. Bartelink
Format: Article
Language:English
Published: Wiley 2025-03-01
Series:CPT: Pharmacometrics & Systems Pharmacology
Online Access:https://doi.org/10.1002/psp4.13299
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Summary:ABSTRACT Prior pharmacokinetic (PK) analysis revealed that increased alpha‐1‐acid glycoprotein (AAG) levels are associated with decreased imatinib unbound fraction in coronavirus disease 2019 (COVID‐19) patients. This study aimed to investigate the PK of total and unbound concentrations of imatinib and the metabolite N‐desmethyl imatinib in hospitalized patients with different severities of COVID‐19, and to assess the impact of critical illness and the potential drug–drug interaction with IL‐6R inhibitors on imatinib exposure. Imatinib, N‐desmethyl imatinib, and AAG were quantified from collected plasma samples. The PK data was further combined with previous data from COVID‐19 patients and chronic myelogenous leukemia/gastrointestinal stromal tumor (CML/GIST) patients who received imatinib. A population PK analysis was conducted using a standard sequential approach. Unbound fraction in COVID‐19 patients admitted to the intensive care unit (ICU) and treated with IL‐6R inhibitors was significantly elevated compared to CML/GIST patients (4.66% vs. 3.54% [1.08%–8.51%]; p < 0.001), despite twofold increased AAG levels. Our findings on total and unbound concentration show that cotreatment with IL‐6R inhibitor can lead to changes in metabolism and protein binding, suggesting similar implications for other highly protein bound drugs. Consequently, total concentrations may not accurately reflect unbound target site concentrations.
ISSN:2163-8306

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