Population pharmacokinetic analysis of doripenem for Japanese patients in intensive care unit.

We aimed to construct a novel population pharmacokinetics (PPK) model of doripenem (DRPM) for Japanese patients in intensive care unit, incorporating the clearance of DRPM by continuous renal replacement therapy (CRRT). Twenty-one patients treated with DRPM (0.25 or 0.5 g) by intravenous infusion over 1 h were included in the study. Nine of the 21 patients were receiving CRRT. Plasma samples were obtained before and 1, 2, 4, 6 and 8 h after the first DRPM administration. PPK analysis was conducted by nonlinear mixed effects modeling using a two-compartment model. Total clearance (CL) in the model was divided into CRRT clearance (CL) and body clearance (CL). The final model was: CL (L h) = CL = 3.65 × (Ccr/62.25) in the absence of CRRT, or = CL + CL = 2.49 × (Ccr/52.75) + CL in the presence of CRRT; CL = Q × 0.919 (0.919 represents non-protein binding rate of DRPM); V (L) = 10.04; V (L) = 8.13; and Q (L h) = 3.53. Using this model, CL was lower and the distribution volumes (V and V) tended to be higher compared to previous reports. Also, Ccr was selected as a significant covariate for CL. Furthermore, the contribution rate of CL to CL was 30-40%, suggesting the importance of drug removal by CRRT. The population analysis model used in this study is a useful tool for planning DRPM regimen and administration. Our novel model may contribute greatly to proper use of DRPM in patients requiring intensive care.