NONMEM population pharmacokinetic and Monte Carlo dosing simulation of ertapenem in patients with sepsis

An alteration of pharmacokinetics (PK) due to pathophysiological changes in patients with critical illnesses have the impact on the drug levels in plasma, consequently affecting the achievement of pharmacodynamics (PD) targets of antibiotics. The objectives of this study were (i) to determine the population PK, and (ii) to assess the probability of target attainment (PTA) of ertapenem in patients with critical conditions. The study examined the population PK of ertapenem using NONMEM and performed the assessment of the PTAs of achieving 40 and 80% of the time that the free drug level exceeds over the MIC (fT>MIC). The central and peripheral volumes of distribution were 49 (with the %CV of 67.10) and 91.90 (with the %CV of 78.90) L, respectively, and total clearance of ertapenem was 15.40 (with the %CV of 46.80) L/h. Our PD analysis for achieving a target of 40% fT>MIC in patients with normal renal function, the dosing of 1 g once daily can cover a MIC of 0.5 mg/L and for a higher minimum inhibitory concentration (MIC) of 1 mg/L, the dosing should be increased to 2 g once daily. Moreover, the achievements of PTAs in patients with lower GFRs were greater than those of PTAs in patients with higher GFRs. In conclusion, higher than maximum recommended dosing of ertapenem may be required for achieving the PD targets in septic patients with critical illnesses; however, in renal impaired patients the required dosage regimens may be lower than recommended dosing. Key words: Pharmacokinetics, pharmacodynamics, ertapenem, sepsis, Monte Carlo simulation.