Boutzoukas Angelique E, Balevic Stephen J, Hemmersbach-Miller Marion, Winokur Patricia L, Gu Kenan, Chan Austin W, Cohen-Wolkowiez Michael, Conrad Thomas, An Guohua, Kirkpatrick Carl M J, Swamy Geeta K, Walter Emmanuel B, Schmader Kenneth E, Landersdorfer Cornelia B
Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
Duke Clinical Research Institute, Durham, NC, USA.
Clin Pharmacokinet. 2025 Feb;64(2):229-241. doi: 10.1007/s40262-024-01465-1. Epub 2024 Dec 16.
We conducted an opportunistic pharmacokinetic study to evaluate the population pharmacokinetics of meropenem, an antimicrobial commonly used to treat Gram-negative infections in adults of different ages, including older adults, and determined optimal dosing regimens.
A total of 99 patients were included. The population pharmacokinetic models used had two compartments: zero-order input and linear elimination. Covariates evaluated included renal function, body size, age, sex, vasopressor use, and frailty, using the Canadian Study of Health and Aging Clinical Frailty score (in patients aged ≥ 65 years). We simulated optimal dosing regimens by renal function and by age group to achieve therapeutic target attainment.
Participants' ages ranged from 20 to 95 years, with an average age of 57.4 years, and 22% (23/103) were aged ≥ 75 years. Creatinine clearance had the greatest impact on the clearance of meropenem. After accounting for renal function and body size, no other covariates resulted in a significant impact on the pharmacokinetics of meropenem. Simulations indicated that patients with normal renal function achieved ≥ 90% target attainment only for organisms with minimum inhibitory concentrations (MICs) ≤ 4 mg/L using the least strict surrogate target of unbound concentration > MIC (fT) for 40% of the dosing interval. For the conservative target fT for 100% of the dosing interval, extended infusion may be required even for organisms with MICs up to 0.25 mg/L. Patients with renal impairment could achieve ≥ 90% target attainment for more resistant organisms, but extended infusion did not increase the MICs up to which target attainment could be achieved.
Meropenem dosing should be based on renal function rather than age. For patients without renal impairment, extended infusion may increase the probability of target attainment.
我们开展了一项机会性药代动力学研究，以评估美罗培南的群体药代动力学。美罗培南是一种常用于治疗不同年龄段（包括老年人）成人革兰氏阴性菌感染的抗菌药物，并确定最佳给药方案。
共纳入99例患者。所使用的群体药代动力学模型有两个房室：零级输入和线性消除。评估的协变量包括肾功能、体型、年龄、性别、血管升压药的使用情况以及虚弱程度，其中年龄≥65岁的患者使用加拿大健康与老龄化临床虚弱评分。我们通过肾功能和年龄组模拟最佳给药方案，以实现治疗目标达成。
参与者年龄在20至95岁之间，平均年龄为57.4岁，22%（23/103）年龄≥75岁。肌酐清除率对美罗培南的清除率影响最大。在考虑肾功能和体型后，没有其他协变量对美罗培南的药代动力学产生显著影响。模拟结果表明，对于肾功能正常的患者，仅当病原体的最低抑菌浓度（MIC）≤4mg/L时，使用最宽松的替代目标（即给药间隔的40%时间内游离浓度＞MIC，fT），才能实现≥90%的目标达成率。对于给药间隔100%时间内的保守目标fT，即使对于MIC高达0.25mg/L的病原体，可能也需要延长输注时间。肾功能受损的患者对于耐药性更强的病原体可以实现≥90%的目标达成率，但延长输注时间并不能提高可实现目标达成率的最高MIC值。
美罗培南的给药应基于肾功能而非年龄。对于没有肾功能损害的患者，延长输注时间可能会增加目标达成的概率。
