Population Pharmacokinetics of Meropenem Across the Adult Lifespan.

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Angelique E Boutzoukas, Stephen J Balevic, Marion Hemmersbach-Miller, Patricia L Winokur, Kenan Gu, Austin W Chan, Michael Cohen-Wolkowiez, Thomas Conrad, Guohua An, Carl M J Kirkpatrick, Geeta K Swamy, Emmanuel B Walter, Kenneth E Schmader, Cornelia B Landersdorfer
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Abstract

Background and objective: 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.

Methods: 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.

Results: 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>MIC) for 40% of the dosing interval. For the conservative target fT>4xMIC 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.

Conclusions: 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.

背景和目的我们开展了一项机会性药代动力学研究,以评估美罗培南(一种常用于治疗不同年龄成人(包括老年人)革兰氏阴性菌感染的抗菌药)的群体药代动力学,并确定最佳给药方案:方法:共纳入 99 名患者。采用的群体药代动力学模型有两个部分:零序输入和线性消除。评估的协变量包括肾功能、体型、年龄、性别、血管加压素使用情况以及体弱情况,使用的是加拿大健康与老龄化研究临床体弱评分(年龄≥ 65 岁的患者)。我们按肾功能和年龄组模拟了最佳用药方案,以达到治疗目标:结果:参与者的年龄从 20 岁到 95 岁不等,平均年龄为 57.4 岁,22% 的参与者(23/103)年龄≥ 75 岁。肌酐清除率对美罗培南的清除率影响最大。在考虑了肾功能和体型后,其他协变量均未对美罗培南的药代动力学产生显著影响。模拟结果表明,肾功能正常的患者在用药间隔 40% 的时间内,使用非结合浓度 > MIC(fT>MIC)这一最不严格的替代目标,仅对最低抑菌浓度(MIC)≤ 4 mg/L 的微生物的目标达标率≥90%。如果在 100%的给药间隔时间内采用 fT>4xMIC 的保守目标,则即使是 MIC 值高达 0.25 mg/L 的微生物也可能需要延长输液时间。对于耐药性较强的微生物,肾功能受损的患者可以达到≥90%的目标值,但延长输注时间并不能提高可达到目标的MIC值:结论:美罗培南的剂量应基于肾功能而非年龄。结论:美罗培南的剂量应根据肾功能而非年龄来确定。对于无肾功能损害的患者,延长输注时间可提高达标概率。
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来源期刊
CiteScore
8.80
自引率
4.40%
发文量
86
审稿时长
6-12 weeks
期刊介绍: Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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