Optimization of meropenem dosage in the critically ill population based on renal function

• Published in: Intensive care medicine 2011-04, Vol.37 (4), p.632-638
• Main Authors: Crandon, Jared L., Ariano, Robert E., Zelenitsky, Sheryl A., Nicasio, Anthony M., Kuti, Joseph L., Nicolau, David P.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Anesthesiology; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacokinetics; Biological and medical sciences; Clinical death. Palliative care. Organ gift and preservation; Connecticut; Creatinine; Creatinine - pharmacokinetics; Critical Care Medicine; Critical Illness; Dose-Response Relationship, Drug; Drug dosages; Emergency Medicine; FDA approval; Female; Hospitals, Urban; Humans; Intensive; Intensive care; Intensive care medicine; Kidney - physiopathology; Kidney Function Tests; Male; Medical research; Medical sciences; Medicine; Medicine & Public Health; Medicine, Experimental; Middle Aged; Monte Carlo Method; Monte Carlo simulation; Original; Pain Medicine; Pathogens; Patients; Pediatrics; Pharmacodynamics; Pharmacokinetics; Pharmacy; Pneumology/Respiratory System; Thienamycins - administration & dosage; Thienamycins - pharmacokinetics
• ISSN: 0342-4642; 1432-1238
• DOI: 10.1007/s00134-010-2105-0

Purpose 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, K 12 , and K 21 were 0.24 L/kg, 0.49 h −1 , and 0.65 h −1 , respectively. K 10 was described by the equation: K 10  = 0.3922 + 0.0025 × CrCl. Model bias and precision were −1.9 and 8.1 mg/L. R 2 , 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% f T > 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.