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(total)) in the model was divided into CRRT clearance (CL(CRRT)) and body clearance (CL(body)). The final model was: CL(total) (L h(−1)) = CL(body(non-CRRT)) = 3.65 × (Ccr/62.25)(0.64) in the absence of CRRT, or = CL(body(CRRT)) + CL(CRRT) = 2.49 × (Ccr/52.75)(0.42) + CL(CRRT) in the presence of CRRT; CL(CRRT) = Q(E) × 0.919 (0.919 represents non-protein binding rate of DRPM); V(1) (L) = 10.04; V(2) (L) = 8.13; and Q (L h(−1)) = 3.53. Using this model, CL(total) was lower and the distribution volumes (V(1) and V(2)) tended to be higher compared to previous reports. Also, Ccr was selected as a significant covariate for CL(body). Furthermore, the contribution rate of CL(CRRT) to CL(total) 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.