Disease-Drug-Drug Interaction of Imatinib in COVID-19 ARDS: A Pooled Population Pharmacokinetic Analysis.

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.