Transporters and Non-CYP Drug Metabolizing Enzymes in Drug Development: Beyond the Guidance Document | An ISSX 2021 Short Course
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This short course aimed to introduce innovative in vitro and in vivo translational approaches and knowledge of transporter clinical probes, endogenous biomarkers, transporter induction, and UGT DDI provided by experts from academia, industry, and regulatory agencies with a focus on: 1) Strategy of utilizing in vitro and in vivo tools for transporter-mediated DDI assessment; 2) Current understanding of preclinical models to study transporter induction; 3) Assessment of UGT-mediated DDI in vitro; and 4) Regulatory perspectives on clinical importance of UGT-mediated DDIs. The knowledge gained from this short course will help DMPK and clinical pharmacology scientists at all levels get familiar with research tools that may be used to understand DDIs involving transporters and non-CYP enzymes (e.g., UGTs). The knowledge learned may be applicable to their respective work in drug development and regulatory review and approvals.
Course Chairs: Lei Zhang, FDA, Silver Spring, Maryland, USA and Ikumi Tamai, Kanazawa University, Kanazawa, Japan
Strategy of Utilizing in vitro and in vivo Tools for Transporter-Mediated Drug-Drug Interaction Assessment: An Industry Perspective 
Hong Shen, Bristol-Myers Squibb, Princeton, New Jersey, USA
Can Transporters be Induced?
Yurong Lai, Gilead Sciences, Foster City, California, USA
In vitro Assessment of the DDI liability of Glucuronidated Drugs: Experimental Approaches for the Characterisation of UDP-glucuronosyltransferase Enzyme Activities and Reaction Phenotyping
John Miners, Flinders University, Adelaide, Australia
Evaluation of DDIs mediated by UGTs: Regulatory Perspectives
Xinning Yang, FDA, Ellicott City, Maryland, USA
Panel Discussion featuring Speakers and Chairs
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Strategy of Utilizing in vitro and in vivo Tools for Transporter-Mediated Drug-Drug Interaction Assessment: An Industry Perspective | Hong Shen, Bristol-Myers Squibb, Princeton, New Jersey, USA
Recorded 07/12/2021
Recorded 07/12/2021
It is well established that various efflux (ATP-binding cassette) and uptake (solute carrier) transporters can govern a drug’s absorption, distribution, metabolism, excretion, and toxicity profiles. Notably, drug interactions may reduce drug transporter activities through inhibition or may increase their activities through induction. For example, organic anion transporting polypeptide 1B (OATP1B) has been described as a "rate-determining step" in hepatic clearance for some dual transporter and enzyme drug substrates. OATP1B1 and OATP1B3 play an important role in the disposition and DDI of a large number of shared substrate drugs, such as HMG-coenzyme A reductase inhibitors (statins), antibiotics, protease inhibitors and anticancer drugs. Consequently, an effort has been made to develop high-throughput in vitro transporter inhibition/substrate screens, in vitro cell-based reagents, and animal models solutions to support data integration. Additionally, in recent years the emerging approaches such as endogenous biomarker, PET imaging, and physiologically based pharmacokinetic (PBPK) modelling provide mechanistic insight into understanding the role of transporters in drug disposition. In conclusion, drug transporter investigation is an essential part of drug discovery and development – and the development of standard methods for further transporter investigation is urgently needed.
Can Transporters be Induced? | Yurong Lai, Gilead Sciences, Foster City, California, USA
Recorded 07/12/2021
Recorded 07/12/2021
The lecture will provide an overview of current understanding on transporter induction. In vitro and in vivo studies of OATP1B, P-gp, and BCRP induction in cynomolgus monkeys and humans will be discussed to determine how preclinical models may be used to predict or understand DDI observed in clinical and whether transporter induction is one of DDI mechanisms that need to be evaluated during drug development.
In vitro Assessment of the DDI liability of Glucuronidated Drugs: Experimental Approaches for the Characterisation of UDP-glucuronosyltransferase Enzyme Activities and Reaction Phenotyping | John Miners, Flinders University, Adelaide, Australia
Recorded 07/12/2021
Recorded 07/12/2021
The UDP-glucuronosyltransferases (UGTs) comprise a superfamily of enzymes that metabolise drugs from almost all therapeutic classes. Among the hepatically expressed family 1 and 2 enzymes, UGT 1A1, 1A9 and 2B7 appear to be of most importance to drug glucuronidation in humans, although UGT 1A3, 1A4, 1A6, 2B4, 2B10, 2B15 and 2B17 also variably contribute to drug clearance. While it was originally believed that drug-drug interactions (DDIs) involving glucuronidated drugs were relatively uncommon, there is increasing evidence that inhibition and induction of UGT enzymes may result in clinically relevant changes in victim drug exposure. Thus, prediction of the DDI liability of an NCE, both as a perpetrator and victim, is an important consideration for drug dosage optimisation in response to inhibition or induction. In addition, in vitro studies are valuable for identifying previously unrecognised DDIs involving established drugs.
UGT enzymes exhibit distinct, but sometimes overlapping, substrate and inhibitor selectivities and differ in terms of regulation of expression. As a result, patterns of DDIs vary between the UGT enzyme(s) involved in drug glucuronidation. Hence, characterisation of the DDI potential of an NCE requires identification of the UGT enzyme(s) responsible for metabolism (reaction phenotyping) and determination of the magnitude of the change in intrinsic clearance. This presentation will focus on the experimental approaches employed for the assessment of DDI liability in vitro, especially in relation to interactions arising from UGT enzyme inhibition, using human liver microsomes, recombinant UGT enzymes, and (less commonly) human hepatocytes as the enzyme sources. Despite the widespread use of in vitro approaches for the measurement of UGT enzyme activities and kinetic parameters in vitro, experimental conditions often vary between laboratories and consequently the interpretation of results can be problematic. However, evidence-based strategies have been published recently [1], and it is anticipated that these will inform practice and guide ongoing research. Similarly, experimental approaches for UGT reaction phenotyping, which quantifies the fractional contribution (fm) of an enzyme to overall metabolism, have advanced significantly in recent years [1]. Availability of the fm together with the inhibition constant (Ki) determined from in vitro inhibition kinetic experiments underpins prediction of the change in victim drug exposure, which in turn informs the need for and design of clinical DDI studies.
[1] JO Miners et al. Pharmacology and Therapeutics. 218: article number 107689 (2021).
Evaluation of DDIs mediated by UGTs: Regulatory Perspectives | Xinning Yang, FDA, Ellicott City, Maryland, USA
Recorded 07/12/2021
Recorded 07/12/2021
Although UDP glucuronosyl transferases (UGTs) have been found to be involved in the metabolism of a number of drugs, there is still a lack of a consensus on how to evaluate the DDI risk mediated by UGTs in drug development. US FDA received comments that the decision framework on evaluating drugs as UGT substrates in the 2012 FDA draft DDI guidance was prescriptive and may limit how UGTs are evaluated during drug development. Therefore, the decision framework was removed from the 2020 final version of the FDA DDI guidance. This removal may be interpreted as an absence of clinically important contributions of UGTs to drug disposition, which is not the case. Thus, this presentation will discuss regulatory perspectives on clinical importance of UGT-mediated DDIs and considerations for deciding the need of in vitro and/or clinical assessments during drug development. Remaining knowledge gaps will be also be described.
Panel Discussion 1 featuring Speakers and Chairs
Recorded 07/12/2021
Recorded 07/12/2021
Featuring
Xinning Yang, FDA, Ellicott City, Maryland, USA
Yurong Lai, Gilead Sciences, Foster City, California, USA
Hong Shen, Bristol-Myers Squibb, Princeton, New Jersey, USA
Lei Zhang, FDA, Silver Spring, Maryland, USA
Panel Discussion 2 featuring Speakers and Chairs
Recorded 07/12/2021
Recorded 07/12/2021
Featuring:
Xinning Yang, FDA, Ellicott City, Maryland, USA
Yurong Lai, Gilead Sciences, Foster City, California, USA
Hong Shen, Bristol-Myers Squibb, Princeton, New Jersey, USA
Lei Zhang, FDA, Silver Spring, Maryland, USA
John Miners, Flinders University, Adelaide, Australia