Pharmacokinetics of doripenem in plasma and epithelial lining fluid (ELF): comparison of two dosage regimens

Abstract

Purpose: In 2014, FDA released a warning for prescription of doripenem for ventilator-associated bacterial pneumonia due to unsatisfactory clinical cure rates. The present study explores if the observed lack of efficacy might be explained by insufficient target site pharmacokinetics in intensive care patients after two different infusion schemes. Methods: Plasma and bronchoalveolar lavage sampling was performed in 16 intubated patients with pneumonia receiving doripenem either as 1-h or as 4-h infusion. Doripenem concentrations were measured at steady state in plasma over 8 h, bronchoalvoelar lavage was performed in each patient once either after 0 h, 2 h, 4 h or 6 h. Results: In plasma, mean values of Cmax, Tmax and AUC0–8 were 16.87 mg/L, 0.69 h and 52.98 mg/L×h after 1 h of infusion, and 12.94 mg/L, 3.21 h and 70.64 mg/L×h after 4 h of infusion, respectively. While the later tmax in plasma was with delay mirrored in the lung, for ELF, much lower concentrations were observed (Cmax, Tmax and AUC0–8 after 1-h infusion of 4.6 mg/L, 2 h and 15.3 mg/L×h and after 4-h infusion 6.9 mg/L, 4 h and 14.8 mg/L×h). Conclusion: The difference in plasma pharmacokinetics after 1-h and 4-h infusion reflects in the concentration versus time profile in the lung, but concentration at the target site was not only considerably lower but also subject to high inter-individual variability. We hypothesise that insufficient concentrations at the target site might have contributed to the previously described lack of clinical efficacy and confirmed the demand for assessment of target site pharmacokinetics in larger patient collectives.