title: Population Pharmacokinetics and Target Attainment of Ertapenem in Plasma and Tissue Assessed via Microdialysis in Morbidly Obese Patients after Laparoscopic Visceral Surgery.
abstract: Ertapenem provides broad-spectrum activity against many pathogens, and its use is relevant for the prophylaxis and treatment of infections in morbidly obese patients undergoing surgery. However, its pharmacokinetics and tissue penetration in these patients are not well defined. We assessed the population pharmacokinetics and target attainment for ertapenem in the plasma, subcutaneous tissue, and peritoneal fluid of morbidly obese patients. Six female patients (body mass index, 43.7 to 55.9 kg/m2) received 1,000 mg ertapenem as 15-min infusions at 0 and 26 h. On day 2, the unbound ertapenem concentrations in plasma, subcutaneous tissue, and peritoneal fluid were measured by microdialysis; total plasma concentrations were additionally quantified. The probability of attaining a target of an unbound ertapenem concentration above the MIC for at least 40% of the dosing interval was predicted via Monte Carlo simulations. The population pharmacokinetic model contained two disposition compartments and simultaneously described all concentrations. For unbound ertapenem, total clearance was 12.3 liters/h (coefficient of variation, 21.6% for between-patient variability) and the volume of distribution at steady state was 57.8 liters in patients with a 53-kg fat-free mass. The area under the concentration-time curve (AUC) for ertapenem was 49% lower in subcutaneous tissue and 25% lower in peritoneal fluid than the unbound AUC in plasma. Tissue penetration was rapid (equilibration half-life, <15 min) and was variable in subcutaneous tissue. Short-term ertapenem infusions (1,000 mg every 24 h) achieved robust (>90%) target attainment probabilities for MICs of up to 1 mg/liter in plasma, 0.25 to 0.5 mg/liter in subcutaneous tissue, and 0.5 mg/liter in peritoneal fluid. Ertapenem presents an attractive choice for many pathogens relevant to morbidly obese patients undergoing surgery. (This study has been registered at ClinicalTrials.gov under identifier NCT01407965.).
authors: Department of Visceral Surgery, University of Ulm, Ulm, Germany mathias.wittau@uniklinik-ulm.de.
authors: Mathias
authors: M
authors: Wittau
authors: Department of Visceral Surgery, University of Ulm, Ulm, Germany.
authors: Stephan
authors: S
authors: Paschke
authors: Department of Clinical Chemistry, University of Ulm, Ulm, Germany.
authors: Max
authors: M
authors: Kurlbaum
authors: Department of Visceral Surgery, University of Ulm, Ulm, Germany.
authors: Jan
authors: J
authors: Scheele
authors: School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
authors: Neang S
authors: 0000-0002-5571-0347
authors: NS
authors: Ly
authors: Department of Visceral Surgery, University of Ulm, Ulm, Germany.
authors: Evelyn
authors: E
authors: Hemper
authors: Department of Visceral Surgery, University of Ulm, Ulm, Germany.
authors: Marko
authors: M
authors: Kornmann
authors: Department of Visceral Surgery, University of Ulm, Ulm, Germany.
authors: Doris
authors: D
authors: Henne-Bruns
authors: Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA.
authors: Jürgen B
authors: JB
authors: Bulitta
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077727:Ertapenem; D005260:Female; D006801:Humans; D010535:Laparoscopy; D008826:Microbial Sensitivity Tests; D017551:Microdialysis; D008875:Middle Aged; D009010:Monte Carlo Method; D009767:Obesity, Morbid / Q000097:blood* / Q000628:therapy; D047090:beta-Lactams / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D000077727:Ertapenem
keywords: Monte Carlo simulation; S-ADAPT; ertapenem; microdialysis; morbidly obese patients; pharmacodynamics; population pharmacokinetics; subcutaneous tissue