Population pharmacokinetic analysis of doripenem for Japanese patients in intensive care unit
Ko Nonoshita, Yosuke Suzuki, Ryota Tanaka, Tetsuya Kaneko, Yoshifumi Ohchi, Yuhki Sato, Norihisa Yasuda, Koji Goto, Takaaki Kitano, Hiroki Itoh
Abstract
Abstract 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.