School of Pharmacy, University of Maryland, Baltimore, Maryland, USA.
Feinberg School of Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois, USA.
Clin Transl Sci. 2020 Mar;13(2):301-308. doi: 10.1111/cts.12710. Epub 2019 Nov 20.
There have been literature reports that some recommended meropenem dosage regimens may fail to meet therapeutic targets in some high-risk children and adults. We evaluated this observation in children using literature studies conducted in infants and children. Observed and, as necessary, simulated data from the literature were combined, yielding a data set of 288 subjects (1 day to ~ 17 years). A population pharmacokinetic model was fit to the data and then used to simulate the recommended dosing regimens and estimate the proportion of subjects achieving recommended target exposures. A two-compartment model best fit the data with weight, postnatal age, gestational age, and serum creatinine as covariates. The US Food and Drug Administration (FDA)-approved dosing regimens achieved targets in ~ 90% or more of subjects less than 3 months of age for organisms with minimum inhibitory concentration (MIC)'s of 2 and 4 mg/L; however, only 68.4% and 41.7% of subjects older than 3 months and weighing < 50 kg achieved target exposures for organisms with MIC's of 2 and 4 mg/L, respectively [Correction added on January 23, 2020, after first online publication: "> 3 months" corrected to "less than 3 months".]. Moreover, for subjects weighing more than 50 kg, only 41.3% and 17% achieved these respective targets. Simulation studies were used to explore the impact of changing dose, dosing interval, and infusion duration on the likelihood of achieving therapeutic targets in these groups. Our findings illustrate that current dosing recommendations for children over 3 months of age fail to meet therapeutic targets in an unacceptable fraction of patients. Further investigation is needed to develop new dosing strategies in these patients.
已有文献报道，一些推荐的美罗培南剂量方案可能无法达到某些高危儿童和成人的治疗目标。我们使用在婴儿和儿童中进行的文献研究来评估这种观察结果。将文献中的观察数据和必要时的模拟数据合并，得到了 288 名受试者的数据（1 天至~17 岁）。拟合了群体药代动力学模型，然后使用该模型模拟推荐的剂量方案并估计达到推荐目标暴露的受试者比例。体重、出生后年龄、胎龄和血清肌酐作为协变量的两室模型最适合数据。美国食品和药物管理局（FDA）批准的剂量方案在 2 和 4mg/L 最小抑菌浓度（MIC）的微生物中，使<3 个月的受试者达到目标暴露的比例约为 90%或更高；然而，只有 68.4%和 41.7%的>3 个月且体重<50kg 的受试者分别达到了 MIC 为 2 和 4mg/L 的微生物的目标暴露[2020 年 1 月 23 日在线发表后更正：“>3 个月”更正为“<3 个月”。]。此外，体重超过 50kg 的受试者中，只有 41.3%和 17%达到了这些目标。模拟研究用于探讨改变剂量、给药间隔和输注持续时间对这些人群达到治疗目标的可能性的影响。我们的研究结果表明，对于>3 个月的儿童，目前的剂量推荐方案无法在无法接受的比例的患者中达到治疗目标。需要进一步研究为这些患者开发新的剂量策略。
