{"title":"应用生理药代动力学模型比较两性霉素B脂质体与常规两性霉素B脱氧胆酸盐在人体内的生物分布。","authors":"Xueyuan Zhang, Yingying Yang, Manman Wang, Huanhuan Qi, Chunlei Li, Limei Zhao","doi":"10.1002/bdd.2406","DOIUrl":null,"url":null,"abstract":"<p><p>Amphotericin B (AmB) has been a cornerstone in the treatment of invasive fungal infections for over 6 decades. Compared with conventional amphotericin B deoxycholate (AmB-DOC), liposomal amphotericin B has comparable efficacy but less nephrotoxicity. The main purpose of this study was to investigate the reason why liposomal amphotericin B has similar therapeutic effects but lower toxicity and the differences of distribution in humans between liposomal amphotericin B and AmB-DOC. To compare the distribution of liposomal amphotericin B and AmB-DOC in humans, the physiologically based pharmacokinetic (PBPK) model was established by bottom-up stepwise method. A rat PBPK model was established firstly, then verified in mouse level in consideration of interspecies differences in physiological- and drug-specific parameters, and finally the PBPK model was extrapolated to humans. Based on preclinical and clinical pharmacokinetic (PK) studies, the AmB-DOC and liposomal amphotericin B PBPK model were established, respectively. The simulated results of human PBPK model showed that the liposomal formulation changed the pharmacokinetic characteristics of AmB. Compared with AmB-DOC, the plasma exposure of liposomal formulation was higher, but the renal exposure was significantly reduced.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":" ","pages":"208-219"},"PeriodicalIF":1.7000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Application of Physiologically Based Pharmacokinetic Model to Compare the Biodistribution of Liposomal Amphotericin B With Conventional Amphotericin B Deoxycholate in Humans.\",\"authors\":\"Xueyuan Zhang, Yingying Yang, Manman Wang, Huanhuan Qi, Chunlei Li, Limei Zhao\",\"doi\":\"10.1002/bdd.2406\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Amphotericin B (AmB) has been a cornerstone in the treatment of invasive fungal infections for over 6 decades. Compared with conventional amphotericin B deoxycholate (AmB-DOC), liposomal amphotericin B has comparable efficacy but less nephrotoxicity. The main purpose of this study was to investigate the reason why liposomal amphotericin B has similar therapeutic effects but lower toxicity and the differences of distribution in humans between liposomal amphotericin B and AmB-DOC. To compare the distribution of liposomal amphotericin B and AmB-DOC in humans, the physiologically based pharmacokinetic (PBPK) model was established by bottom-up stepwise method. A rat PBPK model was established firstly, then verified in mouse level in consideration of interspecies differences in physiological- and drug-specific parameters, and finally the PBPK model was extrapolated to humans. Based on preclinical and clinical pharmacokinetic (PK) studies, the AmB-DOC and liposomal amphotericin B PBPK model were established, respectively. The simulated results of human PBPK model showed that the liposomal formulation changed the pharmacokinetic characteristics of AmB. Compared with AmB-DOC, the plasma exposure of liposomal formulation was higher, but the renal exposure was significantly reduced.</p>\",\"PeriodicalId\":8865,\"journal\":{\"name\":\"Biopharmaceutics & Drug Disposition\",\"volume\":\" \",\"pages\":\"208-219\"},\"PeriodicalIF\":1.7000,\"publicationDate\":\"2024-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biopharmaceutics & Drug Disposition\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/bdd.2406\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/12/25 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biopharmaceutics & Drug Disposition","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/bdd.2406","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/12/25 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Application of Physiologically Based Pharmacokinetic Model to Compare the Biodistribution of Liposomal Amphotericin B With Conventional Amphotericin B Deoxycholate in Humans.
Amphotericin B (AmB) has been a cornerstone in the treatment of invasive fungal infections for over 6 decades. Compared with conventional amphotericin B deoxycholate (AmB-DOC), liposomal amphotericin B has comparable efficacy but less nephrotoxicity. The main purpose of this study was to investigate the reason why liposomal amphotericin B has similar therapeutic effects but lower toxicity and the differences of distribution in humans between liposomal amphotericin B and AmB-DOC. To compare the distribution of liposomal amphotericin B and AmB-DOC in humans, the physiologically based pharmacokinetic (PBPK) model was established by bottom-up stepwise method. A rat PBPK model was established firstly, then verified in mouse level in consideration of interspecies differences in physiological- and drug-specific parameters, and finally the PBPK model was extrapolated to humans. Based on preclinical and clinical pharmacokinetic (PK) studies, the AmB-DOC and liposomal amphotericin B PBPK model were established, respectively. The simulated results of human PBPK model showed that the liposomal formulation changed the pharmacokinetic characteristics of AmB. Compared with AmB-DOC, the plasma exposure of liposomal formulation was higher, but the renal exposure was significantly reduced.
期刊介绍：
Biopharmaceutics & Drug Dispositionpublishes original review articles, short communications, and reports in biopharmaceutics, drug disposition, pharmacokinetics and pharmacodynamics, especially those that have a direct relation to the drug discovery/development and the therapeutic use of drugs. These includes:
- animal and human pharmacological studies that focus on therapeutic response. pharmacodynamics, and toxicity related to plasma and tissue concentrations of drugs and their metabolites,
- in vitro and in vivo drug absorption, distribution, metabolism, transport, and excretion studies that facilitate investigations related to the use of drugs in man
- studies on membrane transport and enzymes, including their regulation and the impact of pharmacogenomics on drug absorption and disposition,
- simulation and modeling in drug discovery and development
- theoretical treatises
- includes themed issues and reviews
and exclude manuscripts on
- bioavailability studies reporting only on simple PK parameters such as Cmax, tmax and t1/2 without mechanistic interpretation
- analytical methods
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