title: Pharmacokinetics of doripenem during high volume hemodiafiltration in patients with septic shock.
abstract: Pharmacokinetics (PK) of doripenem was determined during high volume hemodiafiltration (HVHDF) in patients with septic shock. A single 500 mg dose of doripenem was administered as a 1 hour infusion during HVHDF to 9 patients. Arterial blood samples were collected before and at 30 or 60 minute intervals over 8 hours (12 samples) after study drug administration. Doripenem concentrations were determined by ultrahigh performance liquid chromatography-tandem mass spectrometry. Population PK analysis and Monte Carlo simulation of 1,000 subjects were performed. The median convective volume of HVHDF was 10.3 L/h and urine output during the sampling period was 70 mL. The population mean total doripenem clearance on HVHDF was 6.82 L/h, volume of distribution of central compartment 10.8 L, and of peripheral compartment 12.1 L. Doses of 500 mg every 8 hours resulted in 88.5% probability of attaining the target of 50% time over MIC for bacteria with MIC = 2 µg/mL at 48 hours, when doubling of MIC during that time was assumed. Significant elimination of doripenem occurs during HVHDF. Doses of 500 mg every 8 hours are necessary for treatment of infections caused by susceptible bacteria during extended HVHDF.
authors.affiliation: Clinic of Anaesthesiology and Intensive Care, Tartu University Hospital, Tartu, Estonia; Department of Anaesthesiology and Intensive Care, University of Tartu, Tartu, Estonia.
authors.forename: Kadri
authors.initials: K
authors.lastname: Tamme
authors.forename: Kersti
authors.initials: K
authors.lastname: Oselin
authors.forename: Karin
authors.initials: K
authors.lastname: Kipper
authors.forename: Kaywei
authors.initials: K
authors.lastname: Low
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Standing
authors.forename: Tuuli
authors.initials: T
authors.lastname: Metsvaht
authors.forename: Juri
authors.initials: J
authors.lastname: Karjagin
authors.forename: Koit
authors.initials: K
authors.lastname: Herodes
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kern
authors.forename: Joel
authors.initials: J
authors.lastname: Starkopf
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D015780:Carbapenems / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000077726:Doripenem; D005260:Female; D017583:Hemodiafiltration; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009010:Monte Carlo Method; D012772:Shock, Septic / Q000097:blood* / Q000188:drug therapy / Q000628:therapy*
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000077726:Doripenem
keywords: antibiotics; carbapenems; dosing; intensive care; renal replacement therapy