Department of Pediatrics, University of California San Diego School of Medicine and Rady Children's Hospital of San Diego, San Diego, CA, USA.
Department of Pediatrics, Kharkiv National Medical University, Kharkiv, Ukraine.
J Clin Pharmacol. 2023 Dec;63(12):1387-1397. doi: 10.1002/jcph.2334. Epub 2023 Sep 2.
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 (C ) across age cohorts were 56.5%-93.7% and 32.2-38.2 mcg/mL, respectively. For relebactam, the ranges of the geometric mean C 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.
亚胺培南/西司他丁/雷巴他定获批用于治疗成人严重革兰氏阴性细菌感染。本研究评估了单剂量亚胺培南/西司他丁/雷巴他定（亚胺培南/西司他丁的固定 2:1 比例，雷巴他定的最大剂量为 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 雷巴他定[≤250mg 雷巴他定]）在接受标准抗菌治疗的确诊/疑似革兰氏阴性细菌感染儿童中的药代动力学（PK）、安全性和耐受性。在这项 1 期、非对照研究（ClinicalTrials.gov 标识符：NCT03230916）中，使用群体建模和非房室分析对 46 名儿童的 PK 参数进行了分析。亚胺培南的 PK/药效学（PD）目标是未结合血浆浓度超过最低抑菌浓度（MIC）的给药间隔时间的百分比（%fT>MIC）≥30%（MIC=2mcg/mL）。对于雷巴他定，PK/PD 目标是游离药物浓度时间曲线下面积（AUC）与 MIC（2mcg/mL）归一化的 AUC（在 2mcg/mL 时）≥8.0（相当于从时间 0 外推到无穷大的 AUC 为≥20.52mcg·h/mL）。在药物输注后 14 天内评估安全性。对于亚胺培南，各年龄组的几何均数%fT>MIC 和最大浓度（C ）的范围分别为 56.5%-93.7%和 32.2-38.2mcg/mL。对于雷巴他定，各年龄组的几何均数 C 和 0 至 6 小时的 AUC 范围分别为 16.9-21.3mcg/mL 和 26.1-55.3mcg·h/mL。共有 8/46（17%）名儿童发生了≥1 次不良事件（AE），2/46（4%）名儿童发生了研究者认为与药物相关的非严重 AE。亚胺培南和雷巴他定超过了血浆 PK/PD 目标；单剂量的亚胺培南/西司他丁/雷巴他定耐受良好，未发现明显的安全性问题。这些结果为进一步的儿科临床评估提供了亚胺培南/西司他丁/雷巴他定的剂量选择信息。
