Population Pharmacokinetics and Target Attainment of Ertapenem in Plasma and Tissue Assessed via Microdialysis in Morbidly Obese Patients after Laparoscopic Visceral Surgery [PublishAheadOfPrint]

Ertapenem provides broad-spectrum activity against many pathogens relevant for 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 plasma, subcutaneous tissue and peritoneal fluid of morbidly obese patients. Six female patients (BMI: 43.7-55.9 kg/m²) received 1,000mg ertapenem as 15-min infusions at 0 and 26h. On day 2, unbound ertapenem concentration profiles in plasma, subcutaneous tissue, and peritoneal fluid were measured by microdialysis; total plasma concentrations were additionally quantified. The probability of attaining a target of the unbound ertapenem concentrations 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 12.3L/h (21.6% CV for between patient variability) and volume of distribution at steady-state 57.8L in patients with 53kg fat-free mass. The area under the ertapenem concentration time curve (AUC) was 49% lower in subcutaneous tissue and 25% lower in peritoneal fluid compared to the unbound AUC in plasma. Tissue penetration was rapid (equilibration half-life <15min) and, in subcutaneous tissue, variable. Short-term ertapenem infusions (1,000 mg every 24h) achieved robust (>90%) target attainment probabilities for MICs up to 1 mg/L in plasma, 0.25 to 0.5 mg/L in subcutaneous tissue, and 0.5 mg/L in peritoneal fluid. Ertapenem presents an attractive choice for many pathogens relevant to morbidly obese patients undergoing surgery.

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