کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8513689 | 1556497 | 2018 | 35 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Mechanistic Physiologically Based Pharmacokinetic Modeling of the Dissolution and Food Effect of a Biopharmaceutics Classification System IV Compound-The Venetoclax Story
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کلمات کلیدی
CyPPBPKGLPsDLMCLLUSPAmorphous - آمورفpassive diffusion/transport - انتشار پویا / حمل و نقلUnited States Pharmacopeia - ایالات متحده داروسازیFood effect - تأثیر غذاییDrug interaction - تعاملات داروییIntestinal absorption - جذب رودهBCs - روند BCsCytochrome P450 - سیتوکروم پی۴۵۰biopharmaceutics classification system - سیستم طبقه بندی بیولوژیکی داروpharmacokinetic - فارماکوکینتیکClinical pharmacokinetics - فارماکوکینتیک بالینیphysiologically based pharmacokinetics - فارماکوکینتیک مبتنی بر فیزیولوژی استBioavailability - فراهم زیستیChronic lymphocytic leukemia - لوسمی مزمن لنفوئیدیPhysiologically based pharmacokinetic modeling - مدلسازی فارماکوکینتیک مبتنی بر فیزیولوژیASD - نقص سپتوم یا دیوارهی دهلیزیAmorphous solid dispersion - پراکندگی جامد Amorphous
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Venetoclax, a selective B-cell lymphoma-2 inhibitor, is a biopharmaceutics classification system class IV compound. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to mechanistically describe absorption and disposition of an amorphous solid dispersion formulation of venetoclax in humans. A mechanistic PBPK model was developed incorporating measured amorphous solubility, dissolution, metabolism, and plasma protein binding. A middle-out approach was used to define permeability. Model predictions of oral venetoclax pharmacokinetics were verified against clinical studies of fed and fasted healthy volunteers, and clinical drug interaction studies with strong CYP3A inhibitor (ketoconazole) and inducer (rifampicin). Model verification demonstrated accurate prediction of the observed food effect following a low-fat diet. Ratios of predicted versus observed Cmax and area under the curve of venetoclax were within 0.8- to 1.25-fold of observed ratios for strong CYP3A inhibitor and inducer interactions, indicating that the venetoclax elimination pathway was correctly specified. The verified venetoclax PBPK model is one of the first examples mechanistically capturing absorption, food effect, and exposure of an amorphous solid dispersion formulated compound. This model allows evaluation of untested drug-drug interactions, especially those primarily occurring in the intestine, and paves the way for future modeling of biopharmaceutics classification system IV compounds.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 107, Issue 1, January 2018, Pages 495-502
Journal: Journal of Pharmaceutical Sciences - Volume 107, Issue 1, January 2018, Pages 495-502
نویسندگان
Arian Emami Riedmaier, David J. Lindley, Jeffrey A. Hall, Steven Castleberry, Russell T. Slade, Patricia Stuart, Robert A. Carr, Thomas B. Borchardt, Daniel A.J. Bow, Marjoleen Nijsen,