کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8513682 | 1556497 | 2018 | 38 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
An Investigation of Oral Exposure Variability and Formulation Strategy: A Case Study of PI3Kδ Inhibitor and Physiologically Based Pharmacokinetic Modeling in Beagle Dogs
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کلمات کلیدی
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
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چکیده انگلیسی
It is well acknowledged that drugs with poor aqueous solubility are often associated with poor oral absorption. Fortunately, drugs with a basic pKa can take advantage of solubilization in the stomach under the acidic environment to improve exposure. Consequently, high in vivo variability is often observed when stomach pH is altered. When issue encountered, enabling formulations are often used to solve the problem. However, each enabling formulation has its limitations and the situation can be further complicated by other absorption distribution metabolism elimination parameters. Therefore, formulation strategies need to consider various scenarios in order to be effective. Compound 1 is a potent phosphoinositide 3-kinase delta inhibitor with poor intrinsic solubility and 2 basic pKas. It was dosed as a suspension in dogs and found to have mediocre oral bioavailability with high variability. It was hypothesized that this variability was caused by their stomach pH variability. Pharmacokinetic modeling suggested that the issue could be improved with particle size reduction. Meanwhile, it was found that although the Madin-Darby canine kidney permeability was reasonable, Madin-Darby canine kidney transfected with human MDR1 gene (MDCK-MDR1) suggested that Compound 1 is an efflux transporter substrate. Findings were integrated into the design for in vivo studies in dogs. Data obtained from those studies allowed us to quickly narrow down the formulation approaches.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 107, Issue 1, January 2018, Pages 466-475
Journal: Journal of Pharmaceutical Sciences - Volume 107, Issue 1, January 2018, Pages 466-475
نویسندگان
Po-Chang Chiang, Jodie Pang, Jia Liu, Laurent Salphati,