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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| Format: | Article |
| Language: | English |
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Wiley
2025-03-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.13299 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Medhat M. Said |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6b9173fbfdcc41dc9f1ae8ab6b27f931 |
| institution | DOAJ |
| issn | 2163-8306 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj-art-6b9173fbfdcc41dc9f1ae8ab6b27f9312025-08-20T02:56:39ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062025-03-0114358359510.1002/psp4.13299Disease–Drug–Drug Interaction of Imatinib in COVID‐19 ARDS: A Pooled Population Pharmacokinetic AnalysisMedhat M. Said0Job R. Schippers1Leila Atmowihardjo2Yingxue Li3Mick S. van derPlas4Harm J. Bogaard5Lieuwe D. J. Bos6Ron A. A. Mathôt7Jurjan Aman8Eleonora L. Swart9Imke H. Bartelink10Department of Pharmacy and Clinical Pharmacology Amsterdam UMC, Location VUmc Amsterdam The NetherlandsDepartment of Pulmonary Medicine Amsterdam UMC, Location VUmc Amsterdam The NetherlandsAmsterdam Institute for Infection and Immunity Amsterdam The NetherlandsDepartment of Pharmacy and Clinical Pharmacology Amsterdam UMC, Location VUmc Amsterdam The NetherlandsDepartment of Pharmacy and Clinical Pharmacology Amsterdam UMC, Location VUmc Amsterdam The NetherlandsDepartment of Pulmonary Medicine Amsterdam UMC, Location VUmc Amsterdam The NetherlandsDepartment of Pulmonary Medicine Amsterdam UMC, Location VUmc Amsterdam The NetherlandsAmsterdam Cardiovascular Sciences Amsterdam The NetherlandsDepartment of Pulmonary Medicine Amsterdam UMC, Location VUmc Amsterdam The NetherlandsDepartment of Pharmacy and Clinical Pharmacology Amsterdam UMC, Location VUmc Amsterdam The NetherlandsDepartment of Pharmacy and Clinical Pharmacology Amsterdam UMC, Location VUmc Amsterdam The NetherlandsABSTRACT 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.https://doi.org/10.1002/psp4.13299 |
| spellingShingle | 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 Disease–Drug–Drug Interaction of Imatinib in COVID‐19 ARDS: A Pooled Population Pharmacokinetic Analysis CPT: Pharmacometrics & Systems Pharmacology |
| title | Disease–Drug–Drug Interaction of Imatinib in COVID‐19 ARDS: A Pooled Population Pharmacokinetic Analysis |
| title_full | Disease–Drug–Drug Interaction of Imatinib in COVID‐19 ARDS: A Pooled Population Pharmacokinetic Analysis |
| title_fullStr | Disease–Drug–Drug Interaction of Imatinib in COVID‐19 ARDS: A Pooled Population Pharmacokinetic Analysis |
| title_full_unstemmed | Disease–Drug–Drug Interaction of Imatinib in COVID‐19 ARDS: A Pooled Population Pharmacokinetic Analysis |
| title_short | Disease–Drug–Drug Interaction of Imatinib in COVID‐19 ARDS: A Pooled Population Pharmacokinetic Analysis |
| title_sort | disease drug drug interaction of imatinib in covid 19 ards a pooled population pharmacokinetic analysis |
| url | https://doi.org/10.1002/psp4.13299 |
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