Uwe Liebchen1, Alexander Kratzer2, Sebastian G Wicha3, Frieder Kees4, Charlotte Kloft3, Martin G Kees5. 1. Department of Internal Medicine I, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany. 2. Hospital Pharmacy, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany Department of Pharmaceutical Biology, University of Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany. 3. Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169 Berlin, Germany. 4. Department of Pharmacology, University of Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany. 5. Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169 Berlin, Germany Department of Anaesthesiology and Intensive Care, Charité University Hospital Berlin - Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany martin.kees@charite.de.
Abstract
OBJECTIVES: To determine unbound ertapenem concentrations in plasma and to describe the pharmacokinetics of unbound ertapenem in intensive care unit (ICU) patients. PATIENTS AND METHODS: For assessing the influence of experimental conditions and for development of the ultrafiltration protocol, plasma from healthy volunteers was used. Concentrations of total and unbound ertapenem were determined by HPLC in 29 plasma samples from six ICU patients treated with 1 g of ertapenem once daily. The concentration-time courses were described by a one-compartment model. Ertapenem binding to albumin was assessed by Michaelis-Menten kinetics in solutions of human serum albumin, in plasma from healthy volunteers and in plasma from ICU patients. RESULTS: The unbound fraction (fu) of ertapenem was highly susceptible to pH and temperature during ultrafiltration and was ∼20% in plasma from healthy volunteers at clinically relevant concentrations. In ICU patients, fu was substantially higher (range 30.9%-53.6%). The unbound concentrations of ertapenem exceeded 2 mg/L for 72% (median; range 39%-100%) of the 24 h dosing interval and 0.25 mg/L for 100% (range 79%-100%). The number of binding sites per albumin molecule was 1.22 (95% CI 1.07-1.38) in plasma from healthy volunteers and 0.404 (95% CI 0.158-0.650) in samples from ICU patients. CONCLUSIONS: Determination of unbound ertapenem by ultrafiltration is susceptible to experimental conditions. When determined at physiological pH and temperature, fu of ertapenem is 2- to 4-fold higher than previously reported and even higher in ICU patients. Binding studies indicate that hypoalbuminaemia alone does not explain these differences. This issue should be further investigated for its clinical relevance.
OBJECTIVES: To determine unbound ertapenem concentrations in plasma and to describe the pharmacokinetics of unbound ertapenem in intensive care unit (ICU) patients. PATIENTS AND METHODS: For assessing the influence of experimental conditions and for development of the ultrafiltration protocol, plasma from healthy volunteers was used. Concentrations of total and unbound ertapenem were determined by HPLC in 29 plasma samples from six ICU patients treated with 1 g of ertapenem once daily. The concentration-time courses were described by a one-compartment model. Ertapenem binding to albumin was assessed by Michaelis-Menten kinetics in solutions of human serum albumin, in plasma from healthy volunteers and in plasma from ICU patients. RESULTS: The unbound fraction (fu) of ertapenem was highly susceptible to pH and temperature during ultrafiltration and was ∼20% in plasma from healthy volunteers at clinically relevant concentrations. In ICU patients, fu was substantially higher (range 30.9%-53.6%). The unbound concentrations of ertapenem exceeded 2 mg/L for 72% (median; range 39%-100%) of the 24 h dosing interval and 0.25 mg/L for 100% (range 79%-100%). The number of binding sites per albumin molecule was 1.22 (95% CI 1.07-1.38) in plasma from healthy volunteers and 0.404 (95% CI 0.158-0.650) in samples from ICU patients. CONCLUSIONS: Determination of unbound ertapenem by ultrafiltration is susceptible to experimental conditions. When determined at physiological pH and temperature, fu of ertapenem is 2- to 4-fold higher than previously reported and even higher in ICU patients. Binding studies indicate that hypoalbuminaemia alone does not explain these differences. This issue should be further investigated for its clinical relevance.
Authors: S P van Rijn; M A Zuur; R van Altena; O W Akkerman; J H Proost; W C M de Lange; H A M Kerstjens; D J Touw; T S van der Werf; J G W Kosterink; J W C Alffenaar Journal: Antimicrob Agents Chemother Date: 2017-03-24 Impact factor: 5.191
Authors: Michael Schleibinger; Cathérine L Steinbach; Christoph Töpper; Alexander Kratzer; Uwe Liebchen; Frieder Kees; Bernd Salzberger; Martin G Kees Journal: Br J Clin Pharmacol Date: 2015-06-11 Impact factor: 4.335