Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, 06102, USA.
Intensive Care Med. 2011 Apr;37(4):632-8. doi: 10.1007/s00134-010-2105-0. Epub 2010 Dec 7.
To develop a meropenem population pharmacokinetic model in critically ill patients with particular focus on optimizing dosing regimens based on renal function.
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.
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.
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.
建立重症患者美罗培南群体药代动力学模型，特别关注基于肾功能优化给药方案。
采用肌酐清除率（CrCl）和校正体重进行群体药代动力学分析，以预测参数估算值。对 21 例患者（55 个样本）进行初始建模。对 5 例来自原始模型的随机选择患者的 12 个样本进行验证。采用 5000 例患者的蒙特卡罗模拟来确定三种 CrCl 范围内的最佳给药方案。
平均±标准差年龄、APACHE 和 CrCl 分别为 59.2±16.8 岁、13.6±7 和 78.3±33.7mL/min。美罗培南剂量范围为 0.5 g 每 8 小时（q8h）-2 g q8h，0.5-3 h 输注。中央室容积、K₁₂和 K₂₁的中位数估计值分别为 0.24 L/kg、0.49 h⁻¹和 0.65 h⁻¹。K₁₀ 用方程描述为：K₁₀=0.3922+0.0025×CrCl。模型偏差和精度分别为-1.9 和 8.1mg/L。验证的 R²、偏差和精度分别为 93%、1.1 和 2.6mg/L。在最低抑菌浓度（MIC）高达 8mg/L 时，MIC 达到 40% fT 时的概率分别为 96%、90%和 61%，用于 3h 输注 2g q8h、1g q8h 和 1g q12h，CrCl 值分别为≥50、30-49 和 10-29。这些相同的给药方案作为 0.5h 输注时，目标达成率分别为 75%、65%和 44%。
该药代动力学模型能够准确估计重症患者在广泛 CrCl 值范围内的美罗培南浓度。与 0.5h 输注相比，延长输注时间的方案提高了所有 CrCl 范围内的目标达成率。
