کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2484484 | 1114313 | 2016 | 7 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Clinical Exposure Boost Predictions by Integrating Cytochrome P450 3A4-Humanized Mouse Studies With PBPK Modeling
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کلمات کلیدی
CmaxPBPKDDIHLMRTVAUC - AUCCYP enzymes - آنزیم های CYPdrug metabolizing enzymes - آنزیم های متابولیسم داروdrug-drug interaction - تعامل دارو و داروDrug interaction - تعاملات داروییmaximum plasma concentration - حداکثر غلظت پلاسماElimination - حذفRitonavir - ریتونویرCytochrome P450 - سیتوکروم پی۴۵۰Simulations - شبیهسازی یا سیمولاسیونPharmacokinetics - فارماکوکینتیکClinical pharmacokinetics - فارماکوکینتیک بالینیPhysiologically based pharmacokinetic - فارماکوکینتیک مبتنی بر فیزیولوژیPreclinical pharmacokinetics - فارماکوکینتیک پیشکلامیarea under the plasma concentration-time curve - محدوده تحت منحنی زمان غلظت پلاسماPhysiologically based pharmacokinetic modeling - مدلسازی فارماکوکینتیک مبتنی بر فیزیولوژیInterspecies scaling - مقیاس بین گونه ایProtease inhibitor - مهارکننده پروتئازHepatic clearance - پاکسازی کبد
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
NVS123 is a poorly water-soluble protease 56 inhibitor in clinical development. Data from in vitro hepatocyte studies suggested that NVS123 is mainly metabolized by CYP3A4. As a consequence of limited solubility, NVS123 therapeutic plasma exposures could not be achieved even with high doses and optimized formulations. One approach to overcome NVS123 developability issues was to increase plasma exposure by coadministrating it with an inhibitor of CYP3A4 such as ritonavir. A clinical boost effect was predicted by using physiologically based pharmacokinetic (PBPK) modeling. However, initial boost predictions lacked sufficient confidence because a key parameter, fraction of drug metabolized by CYP3A4 (fmCYP3A4), could not be estimated with accuracy on account of disconnects between in vitro and in vivo preclinical data. To accurately estimate fmCYP3A4 in human, an in vivo boost effect study was conducted using CYP3A4-humanized mouse model which showed a 33- to 56-fold exposure boost effect. Using a top-down approach, human fmCYP3A4 for NVS123 was estimated to be very high and included in the human PBPK modeling to support subsequent clinical study design. The combined use of the in vivo boost study in CYP3A4-humanized mouse model mice along with PBPK modeling accurately predicted the clinical outcome and identified a significant NVS123 exposure boost (â¼42-fold increase) with ritonavir.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 105, Issue 4, April 2016, Pages 1398-1404
Journal: Journal of Pharmaceutical Sciences - Volume 105, Issue 4, April 2016, Pages 1398-1404
نویسندگان
Jin Zhang, Tycho Heimbach, Nico Scheer, Avantika Barve, Wenkui Li, Wen Lin, Handan He,