β-内酰胺酶抑制剂复方制剂非临床研究技术指南  

Technical guidelines for preclinical study ofβ-lactam/β-lactamase inhibitor combinations

作　　者：卞星晨 黄志伟 胡付品 武晓捷[2,3,4] 李鑫 张菁 Bian Xing-chen;Huang Zhi-wei;Hu Fu-pin;Wu Xiao-jie;Li Xin;Zhang Jing(Institute of Antibiotics,Huashan Hospital,Fudan University,Shanghai 200040;Phase Ⅰ Clinical Research Center,Huashan Hospital,Fudan University,Shanghai 200040;Key Laboratory of Clinical Pharmacology,National Health Commission,Shanghai 200040;National Clinical Medical Research Center for Gerontology(Huashan),Shanghai 200040;Chemotherapy Pharmacology Committee of Chinese Pharmacological Society,Zunyi 563003)

机构地区：[1]复旦大学附属华山医院抗生素研究所,上海200040 [2]复旦大学附属华山医院Ⅰ期临床研究中心,上海200040 [3]国家卫健委临床药理重点实验室,上海200040 [4]国家老年疾病临床医学研究中心(华山),上海200040 [5]中国药理学会化疗药理专业委员会,遵义563003

出　　处：《中国抗生素杂志》2023年第1期13-18,共6页Chinese Journal of Antibiotics

基　　金：国家自然科学基金(No.82173896);上海市领军人才(No.LJ2016-01)。

摘　　要：内酰胺酶抑制剂复方制剂在临床上被广泛应用于治疗耐药菌所致感染,由于早期β-内酰胺酶抑制剂的抑酶谱较窄,抑酶谱更广泛的酶抑制剂在不断研发之中。与一般抗菌药物临床前研究不同,β-内酰胺酶抑制剂复方制剂的临床前研究需明确β-内酰胺类药物或酶抑制剂本身的抗菌谱与抗菌活性,尤其是明确酶抑制剂是否具有抗菌活性。需要确定合适的β-内酰胺类药物与酶抑制剂复方制剂,以及适用的不同酶型的目标病原菌。本文主要介绍新型β-内酰胺酶抑制剂复方制剂临床前研究方法。临床前研究阶段的β-内酰胺酶抑制剂复方制剂研究包括体外研究和体内研究两部分,前者主要为体外药效学研究和体外药动学/药效学(pharmacokinetic/pharmacodynamic,PK/PD)研究,常用研究方法包括β-内酰胺类药物和β-内酰胺酶抑制剂复方制剂最低抑菌浓度测定、最低杀菌浓度测定、抗生素后效应测定及时间杀菌曲线。后者主要为动物药动学研究、感染动物药效学研究和感染动物药动学/药效学研究。在动物药动学/药效学研究中,需考虑β-内酰胺类药物与酶抑制剂的相互影响。这些研究方法的应用旨在阐明β-内酰胺酶抑制剂复方制剂两组分药效学特点、药动学相似与否、PK/PD指数及其临床前PK/PD靶值,为进入临床试验阶段目标适应症及剂量选择提供依据。lactam/β-lactamase inhibitor combinations are widely used in clinical treatment of resistant bacterial infections.The early-developedβ-lactamase inhibitors have narrow inhibitory spectrum,those with broader inhibitory spectrums are being developed.Different from general antimicrobials,preclinical studies ofβ-lactam/β-lactamase inhibitor combinations need to clarify the antimicrobial spectrum and activities ofβ-lactam orβ-lactamase inhibitors,especially whetherβ-lactamase inhibitors have antimicrobial activities.It’s necessary to determine the appropriateβ-lactam andβ-lactamase inhibitor combinations,as well as the applicable range of target pathogens with differentβ-lactam types.The technical guidelines mainly introduce preclinical research methods of newβ-lactam/β-lactamase inhibitor combinations.Preclinical studies ofβ-lactam/β-lactamase inhibitor combinations include in vitro and in vivo sections.The former mainly refers to in vitro pharmacodynamics(PD)and pharmacokinetic/pharmacodynamic(PK/PD)studies.Common methods include minimum inhibitory concentration and minimum bactericidal concentration determinations,post-antibiotic effect determination and time-killing curve assay ofβ-lactam/β-lactamase inhibitor combinations.The latter mainly refers to PK studies in animals,PD and PK/PD studies in infected animals.In animal PK/PD studies,the interaction betweenβ-lactams andβ-lactamase inhibitors should be considered.The purpose is to elucidate the pharmacodynamic properties,pharmacokinetic similarities ofβ-lactam andβ-lactamase inhibitor in the studied combination,and to determine the PK/PD indices and preclinical PK/PD target values,and hence to provide basis for target indications and dose selection in clinical trial.

关 键 词：内酰胺酶抑制剂复方制剂 药动学 药效学 药动学/药效学靶值 

分 类 号：R978.1[医药卫生—药品]