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/m 2 ) 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, Ͻ15 min) and was variable in subcutaneous tissue. Short-term ertapenem infusions (1,000 mg every 24 h) achieved robust (Ͼ90%) 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.) KEYWORDS ertapenem, morbidly obese patients, population pharmacokinetics, subcutaneous tissue, microdialysis, S-ADAPT, Monte Carlo simulation, pharmacodynamics E rtapenem covers many bacterial pathogens, and its use is relevant for the prophylaxis and treatment of infections in morbidly obese patients undergoing laparoscopic visceral surgery (1). Ertapenem has a relatively high level of protein binding

Microdialysis as an Important Technique in Systems Pharmacology—a Historical and Methodological Review

“…Target engagement of ertapenem was studied in plasma, subcutaneous tissue, and peritoneal fluid, in morbidly obese patients (108). By performing Monte Carlo simulations and population pharmacokinetic modeling of the microdialysis data, it was found that satisfactory concentrations were reached in all sites, albeit with only 25-50% of the unbound plasma concentration in subcutaneous tissue.…”

Pharmacokinetic-Pharmacodynamic Evaluation of Ertapenem for Patients with Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia

“…Aside from the work described herein, to our knowledge, only three other groups previously utilized nonlinear functions to characterize ertapenem protein binding when conducting ertapenem PK-PD target attainment analyses (30)(31)(32). Additional strengths of these analyses were the utilization of a population PK model which included formally selected covariates and the evaluation of effect-site exposures for patients with HABP/VABP (i.e., ELF AUC values), two considerations which appear to be absent in the available literature describing ertapenem PK-PD target attainment analyses (30)(31)(32)(33)(34)(35)(36)(37). The former consideration allowed for the evaluation of simulated exposures which accounted for the impact of body size and renal function on ertapenem PK.…”

Population Pharmacokinetic Analyses for Ertapenem in Subjects with a Wide Range of Body Sizes

“…It is well established that the pharmacokinetics of ertapenem are impacted by body size (11,12,13). Chen et al (11) conducted noncompartmental analyses using the data described herein.…”

“…Previous studies have demonstrated that ertapenem pharmacokinetic parameters differ considerably in obese and morbidly obese patients relative to values in healthy volunteers (11,12,13). However, functions describing these relationships have not been developed.…”