Pooled population pharmacokinetic model of imipenem in plasma and the lung epithelial lining fluid

AIMS Several clinical trials have confirmed the therapeutic benefit of imipenemfor treatment of lung infections. There is however no knowledge of the penetration of imipenem into the lung epithelial lining fluid (ELF), the site of action relevant for lung infections. Furthermore, although the plasma pharmacokinetics (PK) of imipenem has been widely studied, most studies have been based on selected patient groups. The aim of this analysis was to characterize imipenem plasma PK across populations and to quantify imipenem ELF penetration. METHODS A population model for imipenem plasma PK was developed using data obtained from healthy volunteers, elderly subjects and subjects with renal impairment, in order to identify predictors for inter-individual variability (IIV) of imipenem PK. Subsequently, a clinical study which measured plasma and ELF concentrations of imipenem was included in order to quantify lung penetration. RESULTS A two compartmental model best described the plasma PK of imipenem. Creatinine clearance and body weight were included as subject characteristics predictive for IIV on clearance. Typical estimates for clearance, central and peripheral volume, and inter-compartmental clearance were 11.5 l h(-1), 9.37 l, 6.41 l, 13.7 l h(-1), respectively (relative standard error (RSE) <8%). The distribution of imipenem into ELF was described using a time-independent penetration coefficient of 0.44 (RSE 14%). CONCLUSION The identified lung penetration coefficient confirms the clinical relevance of imipenem for treatment of lung infections, while the population PK model provided insights into predictors of IIV for imipenem PK and may be of relevance to support dose optimization in various subject groups. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Imipenem has therapeutic benefit for treatment of lung infections. Previous pharmacokinetic studies have mainly been based on small and specific patient populations. WHAT THIS STUDY ADDS This is the first integrated analysis of imipenem pharmacokinetics based on a large dataset of healthy volunteers, elderly subjects and subjects with renal impairment. This is the first report on imipenem lung exposure into the epithelial lining fluid. The developed model can be used to optimize imipenem dosing strategies further across patient populations and for treatment of lung infections.