Affiliation:
1. DMPK, IVIVT, GlaxoSmithKline R&D, Stevenage, United Kingdom
2. Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, United Kingdom
Abstract
Membrane transporters play an important role in intestinal absorption, distribution and clearance of
drugs. Additionally transporters along with enzymes regulate tissue exposures (e.g. liver, kidney and brain),
which are important for safety and efficacy considerations. Early identification of transporters involved guides
generation of in vitro and in vivo data needed to gain mechanistic understanding on the role of transporters in organ
clearance, tissue exposures and enables development of physiological-based pharmacokinetic (PBPK) models.
A lot of progress has been made in developing several in vitro assay systems and mechanistic in silico models
to determine kinetic parameters for transporters, which are incorporated into PBPK models. Although, intrinsic
clearance and inhibition data from in vitro systems generally tend to underpredict in vivo clearance and magnitude
of drug-drug interactions (DDIs), empirical scaling factors derived from a sizable dataset are often used
to offset underpredictions. PBPK models are increasing used to predict the impact of transporters on intestinal
absorption, clearance, victim and perpetrator DDIs prior to first in human clinical trials. The models are often
refined when clinical data is available and are used to predict pharmacokinetics in untested scenarios such as
the impact of polymorphisms, ontogeny, ethnicity, disease states and DDIs with other perpetrator drugs. The
aim of this review is to provide an overview of (i) regulatory requirements around transporters, (ii) in vitro systems
and their limitations in predicting transporter mediated drug disposition and DDIs, (iii) PBPK modelling
tactics and case studies used for internal decision making and/or for regulatory submissions.
Publisher
Bentham Science Publishers Ltd.
Subject
Clinical Biochemistry,Pharmacology
Cited by
8 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献