Optimization of meropenem dosage in the critically ill population based on renal function.
OBJECTIVE
To develop a meropenem population pharmacokinetic model in critically ill patients with particular focus on optimizing dosing regimens based on renal function.


METHODS
Population pharmacokinetic analysis was performed with creatinine clearance (CrCl) and adjusted body weight to predict parameter estimates. Initial modeling was performed on 21 patients (55 samples). Validation was conducted with 12 samples from 5 randomly selected patients excluded from the original model. A 5,000-patient Monte Carlo simulation was used to ascertain optimal dosing regimens for three CrCl ranges.


RESULTS
Mean ± SD age, APACHE, and CrCl were 59.2 ± 16.8 years, 13.6 ± 7, and 78.3 ± 33.7 mL/min. Meropenem doses ranged from 0.5 g every 8 h (q8h)-2 g q8h as 0.5-3 h infusions. Median estimates for volume of the central compartment, K₁₂ and K₂₁ were 0.24 L/kg, 0.49 h⁻¹, and 0.65 h⁻¹, respectively. K₁₀ was described by the equation: K₁₀= 0.3922 + 0.0025 × CrCl. Model bias and precision were -1.9 and 8.1 mg/L. R², bias, and precision for the validation were 93%, 1.1, and 2.6 mg/L. At minimum inhibitory concentrations (MICs) up to 8 mg/L, the probability of achieving 40% fT > MIC was 96, 90, and 61% for 3 h infusions of 2 g q8h, 1 g q8h, and 1 g q12h in patients with CrCl ≥50, 30-49, and 10-29, respectively. Target attainment was 75, 65, and 44% for these same dosing regimens as 0.5 h infusions.


CONCLUSIONS
This pharmacokinetic model is capable of accurately estimating meropenem concentrations in critically ill patients over a range of CrCl values. Compared with 0.5 h infusions, regimens employing prolonged infusions improved target attainment across all CrCl ranges.
Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, 06102, USA.
Jared L
JL
Crandon
Robert E
RE
Ariano
Sheryl A
SA
Zelenitsky
Anthony M
AM
Nicasio
Joseph L
JL
Kuti
David P
DP
Nicolau
D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003237:Connecticut; D003404:Creatinine / Q000493:pharmacokinetics; D016638:Critical Illness; D004305:Dose-Response Relationship, Drug; D005260:Female; D006786:Hospitals, Urban; D006801:Humans; D007668:Kidney / Q000503:physiopathology*; D007677:Kidney Function Tests; D008297:Male; D000077731:Meropenem; D008875:Middle Aged; D009010:Monte Carlo Method; D013845:Thienamycins / Q000008:administration & dosage* / Q000493:pharmacokinetics
D000900:Anti-Bacterial Agents; D013845:Thienamycins; D003404:Creatinine; D000077731:Meropenem