Comparative Plasma and Interstitial Tissue Fluid Pharmacokinetics of Meropenem Demonstrate the Need for Increasing Dose and Infusion Duration in Obese and Non-obese Patients

Background and Objectives A quantitative evaluation of the PK of meropenem, a broad-spectrum β-lactam antibiotic, in plasma and interstitial space fluid (ISF) of subcutaneous adipose tissue of obese patients is lacking as of date. The objective of this study was the characterisation of meropenem population pharmacokinetics in plasma and ISF in obese and non-obese patients for identification of adequate dosing regimens via Monte-Carlo simulations. Methods We obtained plasma and microdialysate concentrations after administration of meropenem 1000 mg to 15 obese and 15 non-obese surgery patients from a prospective clinical trial. After characterizing plasma- and microdialysis-derived ISF pharmacokinetics via population pharmacokinetic analysis, we simulated thrice-daily (TID) meropenem short-term (0.5 h), prolonged (3.0 h), and continuous infusions. Adequacy of therapy was assessed by the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment (PTA) analysis based on time unbound concentrations exceeded minimum inhibitory concentrations (MIC) on treatment day 1 (% f T > MIC ) and the sum of PTA weighted by relative frequency of MIC values for infections by pathogens commonly treated with meropenem. To avoid interstitial tissue fluid concentrations below MIC for the entire dosing interval during continuous infusions, a more conservative PK/PD index was selected (% f T > 4 × MIC ). Results Adjusted body weight (ABW) and calculated creatinine clearance (CLCR CG_ABW ) of all patients (body mass index [BMI] = 20.5–81.5 kg/m 2 ) explained a considerable proportion of the between-patient pharmacokinetic variability (15.1–31.0% relative reduction). The ISF:plasma ratio of % f T > MIC was relatively similar for MIC ≤ 2 mg/L but decreased for MIC = 8 mg/L over ABW = 60–120 kg (0.50–0.20). Steady-state concentrations were 2.68 times (95% confidence interval [CI] = 2.11–3.37) higher in plasma than in ISF, supporting PK/PD targets related to four times the MIC during continuous infusions to avoid suspected ISF concentrations constantly below the MIC. A 3000 mg/24 h continuous infusion was sufficient at MIC = 2 mg/L for patients with CLCR CG_ABW ≤ 100 mL/min and ABW < 90 kg, whereas 2000 mg TID prolonged infusions were adequate for those with CLCR CG_ABW ≤ 100 mL/min and ABW > 90 kg. For MIC = 2 mg/L and % f T > MIC = 95, PTA was adequate in patients over the entire investigated range of body mass and renal function using a 6000 mg continuous infusion.