title: Population Pharmacokinetics and Target Attainment of Meropenem in Plasma and Tissue of Morbidly Obese Patients after Laparoscopic Intraperitoneal Surgery.
abstract: Meropenem serves as a clinically important, broad-spectrum antibiotic. While meropenem is commonly used in obese patients, its pharmacokinetics in this patient group is not well known. Our aim was to characterize the population pharmacokinetics and target attainment in plasma, subcutaneous tissue, and peritoneal fluid for meropenem in morbidly obese patients. Four doses of 1g meropenem were given as 15-min infusions every 8 h to five morbidly obese patients (body mass index [BMI], 47.6 to 62.3 kg/m(2)). After the fourth dose, serial meropenem concentrations were determined in plasma and, via microdialysis, in subcutaneous tissue and peritoneal fluid. All concentrations were analyzed simultaneously via population modeling, and target attainment probabilities predicted via Monte Carlo simulations using the target of unbound meropenem concentrations above the MIC for at least 40% of the dosing interval. For patients with 53 kg fat-free mass, total clearance was 18.7 liters/h and volume of distribution at steady state was 27.6 liters. The concentrations in subcutaneous tissue and peritoneal fluid largely paralleled those in plasma (equilibration half-life, <30 min). The area under the curve (AUC) in subcutaneous tissue divided by the plasma AUC had a mean of 0.721. For peritoneal fluid, this AUC ratio had a mean of 0.943. Target attainment probabilities were >90% after 1 g meropenem every 8 h as a 15-min infusion for MICs of up to 2 mg/liter in plasma and peritoneal fluid and 0.5 mg/liter in subcutaneous tissue. Meropenem pharmacokinetics in plasma and peritoneal fluid of obese patients was predictable, but subcutaneous tissue penetration varied greatly. (This study has been registered at ClinicalTrials.gov under registration no. NCT01407965.).
authors.affiliation: Department of Visceral Surgery, University of Ulm, Ulm, Germany mathias.wittau@uniklinik-ulm.de.
authors.forename: Mathias
authors.initials: M
authors.lastname: Wittau
authors.affiliation: Department of Visceral Surgery, University of Ulm, Ulm, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Scheele
authors.affiliation: Department of Clinical Chemistry, University of Ulm, Ulm, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Kurlbaum
authors.affiliation: Department of Visceral Surgery, University of Ulm, Ulm, Germany.
authors.forename: Claas
authors.initials: C
authors.lastname: Brockschmidt
authors.affiliation: Department of Visceral Surgery, University of Ulm, Ulm, Germany.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Wolf
authors.affiliation: Department of Visceral Surgery, University of Ulm, Ulm, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Hemper
authors.affiliation: Department of Visceral Surgery, University of Ulm, Ulm, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Henne-Bruns
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria, Australia.
authors.forename: Jürgen B
authors.initials: JB
authors.lastname: Bulitta
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001202:Ascitic Fluid / Q000737:chemistry / Q000378:metabolism; D001682:Biological Availability; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D010535:Laparoscopy; D008297:Male; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D017551:Microdialysis; D008875:Middle Aged; D009010:Monte Carlo Method; D009767:Obesity, Morbid / Q000188:drug therapy* / Q000378:metabolism* / Q000382:microbiology / Q000601:surgery; D010529:Peritoneal Cavity / Q000382:microbiology / Q000601:surgery; D011446:Prospective Studies; D040521:Subcutaneous Tissue / Q000737:chemistry / Q000378:metabolism; D013845:Thienamycins / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem