Abstract：
Imipenem/cilastatin/relebactam is approved for the treatment of serious gram-negative bacterial infections in adults. This study assessed the pharmacokinetics (PK), safety, and tolerability of a single dose of imipenem/cilastatin/relebactam (with a fixed 2:1 ratio of imipenem/cilastatin to relebactam, and with a maximum dose of 15 mg/kg imipenem and 15 mg/kg cilastatin [≤500 mg imipenem and ≤500 mg cilastatin] and 7.5 mg/kg relebactam [≤250 mg relebactam]) in children with confirmed/suspected gram-negative bacterial infections receiving standard-of-care antibacterial therapy. In this phase 1, noncomparative study (ClinicalTrials.gov identifier, NCT03230916), PK parameters from 46 children were analyzed using both population modeling and noncompartmental analysis. The PK/pharmacodynamic (PD) target for imipenem was percent time of the dosing interval that unbound plasma concentration exceeded the minimum inhibitory concentration (%fT>MIC) of ≥30% (MIC = 2 mcg/mL). For relebactam, the PK/PD target was a free drug area under the plasma concentration-time curve (AUC) normalized to MIC (at 2 mcg/mL) of ≥8.0 (equivalent to an AUC from time zero extrapolated to infinity of ≥20.52 mcg·h/mL). Safety was assessed up to 14 days after drug infusion. For imipenem, the ranges for the geometric mean %fT>MIC and maximum concentration (Cmax ) across age cohorts were 56.5%-93.7% and 32.2-38.2 mcg/mL, respectively. For relebactam, the ranges of the geometric mean Cmax and AUC from 0 to 6 hours across age cohorts were 16.9-21.3 mcg/mL and 26.1-55.3 mcg·h/mL, respectively. In total, 8/46 (17%) children experienced ≥1 adverse events (AEs) and 2/46 (4%) children experienced nonserious AEs that were deemed drug related by the investigator. Imipenem and relebactam exceeded plasma PK/PD targets; single doses of imipenem/cilastatin/relebactam were well tolerated with no significant safety concerns identified. These results informed imipenem/cilastatin/relebactam dose selection for further pediatric clinical evaluation.
摘要：
亚胺培南/西司他丁/雷巴坦被批准用于治疗成人严重的革兰氏阴性菌感染。这项研究评估了药代动力学（PK），安全,和单剂量亚胺培南/西司他丁/来巴坦的耐受性（亚胺培南/西司他丁与来巴坦的固定比例为2：1，最大剂量为15mg/kg亚胺培南和15mg/kg西司他丁[≤500mg亚胺培南和≤500mg西司他丁]和7.5mg/kg瑞利巴坦[≤250mg瑞利巴坦]）在确诊/疑似革兰氏阴性菌感染的儿童中接受标准护理抗菌治疗。在此第一阶段，非比较研究(ClinicalTrials.gov标识符，NCT03230916),亚胺培南的PK/药效学(PD)目标是未结合的血浆浓度超过≥30%(MIC=2μg/mL)的最小抑制浓度(%fT>MIC)的给药间隔的时间百分比.为了释放巴坦，PK/PD目标是浓度-时间曲线下的游离面积（AUC）归一化为MIC（2μg/mL）≥8.0（相当于AUC从0外推至无穷大≥20.52μg·h/mL），分别。在药物输注后长达14天评估安全性。对于亚胺培南，几何平均值%fT>MIC和最大浓度(Cmax)的范围是56.5%-93.7%和32.2-38.2μg/mL，分别。为了释放巴坦，从0到6小时，各年龄组的几何平均Cmax和AUC的范围为16.9-21.3μg/mL和26.1-55.3μg·h/mL，分别。8/46（17％）儿童经历了≥1次不良事件，2/46（4％）儿童经历了研究者认为与药物相关的非严重不良事件。亚胺培南和雷巴坦超过了血浆PK/PD目标；单剂量亚胺培南/西司他丁/雷巴坦的耐受性良好，没有发现明显的安全性问题。这些结果为亚胺培南/西司他丁/雷巴坦的剂量选择提供了信息，以进行进一步的儿科临床评估。本文受版权保护。保留所有权利。
