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

Summary

Pooled population PK across COVID-19 and oncology cohorts shows that IL-6R inhibitors increase imatinib’s unbound fraction in ICU COVID-19 patients despite higher AAG, indicating altered metabolism and protein binding. Reliance on total concentrations may misestimate target-site exposure for imatinib and other highly protein-bound drugs.

Key Findings

• In ICU COVID-19 patients receiving IL-6R inhibitors, imatinib unbound fraction was significantly higher than in CML/GIST patients (4.66% vs 3.54% [1.08%–8.51%]; p<0.001).
• Despite approximately twofold higher AAG levels, co-treatment with IL-6R inhibitors altered imatinib metabolism and protein binding.
• Total plasma concentrations may not reflect unbound target-site concentrations for imatinib and similar highly protein-bound drugs.

Clinical Implications

Consider unbound (free) drug monitoring or adjusted interpretation of total levels when IL-6R inhibitors are co-administered in COVID-19 ARDS; extrapolate caution to other highly protein-bound agents in ICU.

Limitations

• Observational design with heterogeneous cohorts; causality cannot be established.
• Clinical outcome impact and dosing adjustments were not evaluated prospectively.

Future Directions

Prospective studies incorporating unbound therapeutic drug monitoring and evaluating clinical outcomes; assess generalizability to other highly protein-bound ICU drugs.