Pettit Rebecca S, Neu Natalie, Cies Jeffrey J, Lapin Craig, Muhlebach Marianne S, Novak Kimberly J, Nguyen Sean T, Saiman Lisa, Nicolau David P, Kuti Joseph L
Department of Pharmacy, Riley Hospital for Children, Indianapolis, IN, USA.
Department of Pediatrics, Division of Infectious Diseases, Columbia University Medical Center and New York-Presbyterian Morgan Stanley Children's Hospital, New York, NY, USA.
J Antimicrob Chemother. 2016 Jan;71(1):189-95. doi: 10.1093/jac/dkv289. Epub 2015 Sep 27.
Meropenem is frequently used to treat pulmonary exacerbations in children with cystic fibrosis (CF) in the USA. Prolonged-infusion meropenem improves the time that free drug concentrations remain above the MIC (fT> MIC) in adults, but data in CF children are sparse. We describe the population pharmacokinetics, tolerability and treatment burden of prolonged-infusion meropenem in CF children.
Thirty children aged 6-17 years with a pulmonary exacerbation received 40 mg/kg meropenem every 8 h; each dose was administered as a 3 h infusion. Pharmacokinetics were determined using population methods in Pmetrics. Monte Carlo simulation was employed to compare 0.5 with 3 h infusions to estimate the probability of pharmacodynamic target attainment (PTA) at 40% fT> MIC. NCT#01429259.
A two-compartment model fitted the data best with clearance and volume predicted by body weight. Clearance and volume of the central compartment were 0.41 ± 0.23 L/h/kg and 0.30 ± 0.17 L/kg, respectively. Half-life was 1.11 ± 0.38 h. At MICs of 1, 2 and 4 mg/L, PTAs for the 0.5 h infusion were 87.6%, 70.1% and 35.4%, respectively. The prolonged infusion increased PTAs to >99% for these MICs and achieved 82.8% at 8 mg/L. Of the 30 children, 18 (60%) completed treatment with prolonged infusion; 5 did so at home without any reported burden. Nine patients were changed to a 0.5 h infusion when discharged home.
In these CF children, meropenem clearance was greater compared with published values from non-CF children. Prolonged infusion provided an exposure benefit against pathogens with MICs ≥1 mg/L, was well tolerated and was feasible to administer in the hospital and home settings, the latter depending on perception and family schedule.
在美国，美罗培南常用于治疗囊性纤维化（CF）儿童的肺部加重期。延长输注时间的美罗培南可提高成人游离药物浓度高于最低抑菌浓度（fT > MIC）的时间，但CF儿童的数据较少。我们描述了延长输注时间的美罗培南在CF儿童中的群体药代动力学、耐受性和治疗负担。
30名6 - 17岁肺部加重期的儿童每8小时接受40 mg/kg美罗培南治疗；每剂药物输注3小时。使用Pmetrics中的群体方法确定药代动力学。采用蒙特卡洛模拟比较0.5小时和3小时输注，以估计在fT > MIC为40%时达到药效学靶点的概率（PTA）。NCT#01429259。
二室模型最能拟合数据，清除率和容积由体重预测。中央室的清除率和容积分别为0.41±0.23 L/h/kg和0.30±0.17 L/kg。半衰期为1.11±0.38小时。在最低抑菌浓度为1、2和4 mg/L时，0.5小时输注的PTA分别为87.6%、70.1%和35.4%。延长输注使这些最低抑菌浓度下的PTA提高到>99%，在8 mg/L时达到82.8%。30名儿童中，18名（60%）完成了延长输注治疗；5名在家中完成治疗，未报告有任何负担。9名患者出院回家时改为0.5小时输注。
在这些CF儿童中，美罗培南的清除率高于非CF儿童的已发表值。延长输注对最低抑菌浓度≥1 mg/L的病原体具有暴露优势，耐受性良好，在医院和家庭环境中给药均可行，后者取决于认知和家庭时间表。
