Abstract：
:It is understood that a potential issue for drugs with poor aqueous solubility is low oral absorption. If oral exposure issues arise when working with a low solubility drug candidate, the common action is to rely on enabling formulations to solve the issue. However, this approach becomes troublesome in the pre-clinical setting where compound absorption, distribution, metabolism, excretion properties are suboptimal and more factors limiting bioavailability may be at play. A narrow focus on solubility enhancement without a full understanding of compound absorption, distribution, metabolism, excretion properties can produce data that cloak the actual phenomena driving exposure. Compound 1 is a potent and selective PI3Kdelta inhibitor with poor aqueous solubility. In a pharmacokinetic study on dogs, exposure was found to be less than dose-linear. Besides the solubility, further investigations were conducted to identify other factors limiting oral exposure. It was observed that these limiting factors are dose dependent. Results from modeling pharmacokinetic under low-dose conditions suggest that exposure is significantly limited by metabolism and no exposure improvements should be expected from enabled formulations. Furthermore, enabling formulations are expected to exert a beneficial influence at higher doses. An in vivo test was conducted in dogs to verify this phenomenon.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Chiang PC,Sutherlin D,Pang J,Salphati Ldoi
10.1016/j.xphs.2016.04.003subject
Has Abstractpub_date
2016-06-01 00:00:00pages
1802-1809issue
6eissn
0022-3549issn
1520-6017pii
S0022-3549(16)41371-7journal_volume
105pub_type
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