title: Population Pharmacokinetic Analysis of Doripenem after Intravenous Infusion in Korean Patients with Acute Infections.
abstract: We investigated the population pharmacokinetics (PK) of doripenem in Korean patients with acute infections and determined an appropriate dosing regimen using a Monte Carlo simulation for predicting pharmacodynamics (PD). Patients (n= 37) with a creatinine clearance (CLCR) of 20 to 50 ml/min or >50 ml/min who received a 250-mg or 500-mg dose of doripenem over the course of 1 h every 8 h, respectively, were included in this study. Blood samples were taken predosing and 0 h, 0.5 h, and 4 to 6 h after the fourth infusion. A nonlinear mixed-effect modeling tool was used for the PK analysis and pharmacodynamic simulation; doripenem PK were well described by a one-compartment model. The population mean values of the body weight (WT)-normalized clearance (CL/WT) and the body weight-normalized volume of distribution (V/WT) were 0.109 liter/h/kg of body weight (relative standard error, 9.197%) and 0.280 liter/kg (relative standard error, 9.56%), respectively. Doripenem CL was significantly influenced by CLCRThe proposed equation to estimate doripenem CL in Korean patients was CL/WT = 0.109 × WT × (CLCR/57)0.688, where CL/WT is in liters per hour per kilogram. CL in Korean patients was expected to be lower than that in Caucasian patients, regardless of renal function. The Monte Carlo simulation showed that 90% attainment of target PK/PD magnitudes could be achieved with the usual dosing regimens when the MIC was ≤1 mg/liter. However, prolonged infusions (4 h) should be considered, especially when patients have augmented renal function and for patients infected with pathogens with a high MIC. Our results provide an individualized doripenem dosing regimen for patients with various renal functions and for patients infected with bacteria with decreased susceptibility.
authors.affiliation: Department of Clinical Pharmacology, Pusan National University Hospital, Busan, Republic of Korea.|(Bio)Medical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.
authors.forename: Dong-Hwan
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
authors.forename: Yong Kyun
authors.initials: YK
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Keimyung University Dongsan Medical Center, Daegu, Republic of Korea.
authors.forename: Kyubok
authors.initials: K
authors.lastname: Jin
authors.affiliation: Division of Hemato-Oncology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
authors.forename: Myoung Joo
authors.initials: MJ
authors.lastname: Kang
authors.affiliation: Division of Hemato-Oncology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
authors.forename: Young-Don
authors.initials: YD
authors.lastname: Joo
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
authors.forename: Yang Wook
authors.initials: YW
authors.lastname: Kim
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
authors.forename: Young Soo
authors.initials: YS
authors.lastname: Moon
authors.affiliation: Department of Clinical Pharmacology, Inje University College of Medicine, Busan, Republic of Korea.
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea smkimkor@paik.ac.kr.
authors.forename: Sungmin
authors.initials: S
authors.lastname: Kiem
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy*; D015780:Carbapenems / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood; D000077726:Doripenem; D005260:Female; D005919:Glomerular Filtration Rate / Q000502:physiology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D056910:Republic of Korea
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D003404:Creatinine; D000077726:Doripenem
keywords: MIC; Monte Carlo simulation; augmented renal function; clearance; doripenem; population pharmacokinetics; probability of target attainment; prolonged infusion