洛哌丁胺对利托那韦口服多西他赛的药代动力学和组织处置的影响;临床前评估。

IF 2.7 4区 医学 Q3 ONCOLOGY Cancer Chemotherapy and Pharmacology Pub Date : 2024-07-01 Epub Date: 2024-03-08 DOI:10.1007/s00280-024-04662-8
Nancy H C Loos, Viët Bui, Daniëlle H de Jong, Maria C Lebre, Hilde Rosing, Jos H Beijnen, Alfred H Schinkel
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引用次数: 0

摘要

目的:一种由细胞色素 P450(CYP)3 A 抑制剂利托那韦增强的口服多西他赛制剂 ModraDoc006/r 目前正在接受临床研究。根据临床数据,与传统的静脉给药相比,这种口服多西他赛制剂会增加 1-2 级腹泻的发生率。洛哌丁胺是一种常用的腹泻抑制剂,可添加到治疗方案中作为对症治疗。然而,洛哌丁胺也是CYP3A酶的底物,这可能会导致利托那韦和洛哌丁胺竞争这种蛋白质。因此,我们想知道同时服用洛哌丁胺对利托那韦口服多西他赛药代动力学的影响:方法:我们给接受利托那韦和多西他赛口服药的人源化 CYP3A4 小鼠(在肝脏和肠道中表达)同时或延迟 8 小时服用洛哌丁胺。测定了多西他赛、利托那韦、洛哌丁胺及其两种活性代谢物的浓度:结果:在洛哌丁胺治疗期间,多西他赛的血浆暴露量(AUC 和 Cmax)没有变化,利托那韦的血浆药代动力学也没有变化。然而,利托那韦的肝脏和肠道处置在同时服用洛哌丁胺组发生了一些变化,而在8小时服用洛哌丁胺组没有发生变化,这可能是由于洛哌丁胺引起的药物吸收延迟所致。洛哌丁胺本身的药代动力学似乎不受利托那韦的影响:这些结果表明,在利托那韦口服多西他赛治疗中可以加入延迟服用洛哌丁胺,而不会影响多西他赛的总体全身暴露。
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Impact of loperamide on the pharmacokinetics and tissue disposition of ritonavir-boosted oral docetaxel therapy; a preclinical assessment.

Purpose: An oral docetaxel formulation boosted by the Cytochrome P450 (CYP) 3 A inhibitor ritonavir, ModraDoc006/r, is currently under clinical investigation. Based on clinical data, the incidence of grade 1-2 diarrhea is increased with this oral docetaxel formulation compared to the conventional intravenous administration. Loperamide, a frequently used diarrhea inhibitor, could be added to the regimen as symptomatic treatment. However, loperamide is also a substrate of the CYP3A enzyme, which could result in competition between ritonavir and loperamide for this protein. Therefore, we were interested in the impact of coadministered loperamide on the pharmacokinetics of ritonavir-boosted oral docetaxel.

Methods: We administered loperamide simultaneously or with an 8-hour delay to humanized CYP3A4 mice (with expression in liver and intestine) receiving oral ritonavir and docetaxel. Concentrations of docetaxel, ritonavir, loperamide and two of its active metabolites were measured.

Results: The plasma exposure (AUC and Cmax) of docetaxel was not altered during loperamide treatment, nor were the ritonavir plasma pharmacokinetics. However, the hepatic and intestinal dispositions of ritonavir were somewhat changed in the simultaneous, but not 8-hour loperamide treatment groups, possibly due to loperamide-induced delayed drug absorption. The pharmacokinetics of loperamide itself did not seem to be influenced by ritonavir.

Conclusion: These results suggest that delayed loperamide administration can be added to ritonavir-boosted oral docetaxel treatment, without affecting the overall systemic exposure of docetaxel.

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来源期刊
CiteScore
6.10
自引率
3.30%
发文量
116
审稿时长
2.5 months
期刊介绍: Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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