Population pharmacokinetics of unbound imipenem in critically ill patients: a comparison of five renal function estimators for PK/PD-guided dosing.

BACKGROUND

Optimizing imipenem therapy in intensive care patients presents challenges due to pathophysiological changes affecting drug disposition. This study developed a population pharmacokinetics model, determined optimal dosing strategies, and described the observed pharmacokinetic/pharmacodynamic (PK/PD) target attainment and clinical outcomes.

METHODS

Critically ill patients receiving imipenem/cilastatin were enrolled prospectively. Five blood samples per patient were collected within 24-48 h of treatment initiation. Nonlinear mixed-effects modeling characterized drug pharmacokinetics, with Monte Carlo simulations assessing target attainment probabilities.

RESULTS

The study enrolled 21 critically ill patients. A two-compartment model with first-order elimination optimally described imipenem pharmacokinetics, with estimated parameters including total clearance (8.75 L/h), intercompartmental clearance (15.9 L/h), central volume (15.2 L), and peripheral volume (23.4 L). Among evaluated covariates, only estimated glomerular filtration rate (using CKD-EPI 2021 equation) significantly influenced drug clearance. Probability of target attainment analysis (PTA) demonstrated that conventional dosing regimens provided ≥ 90% probability of achieving 40% free time above MIC (fT > MIC) for organisms with MIC values ≤ 2 mg/L. Achieving 75% fT > MIC required maximum conventional doses, whereas 100% fT > MIC with adequate PTA (≥ 80%) necessitated continuous infusion strategies employing doses 30-50% above standard recommendations. Clinical success was observed in 23% of patients (3/13), with higher fT > MIC values among successful cases. However, treatment failure still occurred in some patients despite achieving 100% fT > MIC, suggesting multifactorial determinants of outcomes in critically ill patients.

CONCLUSION

Renal function significantly influences imipenem clearance. While standard dosing provides sufficient coverage for conventional PK/PD targets, continuous infusions should be considered for more aggressive targets.