2018

For more articles, please visit our blog

Published:  31 December 2018

For further discussion of some of the publications below as well as additional articles that we publish on our website and other locations that are not peer-reviewed publications, please visit our blog. You may also be interested in our webinar series and posters.

Chapter 6: Biotransformation of Xenobiotics

Published:  07 December 2018

(estimated publish date only; in final proofing stage)

Andrew Parkinson, Brian W. Ogilvie, David B. Buckley, Faraz Kazmi and Oliver Parkinson
This book chapter will be part of Casarett and Doull's Toxicology: The Basic Science of Poisons, 9th Edition, Edited by Curtis Klaassen. McGraw-Hill Medical Pub. Division, New York. ISBN-13: 978-1-259-86374-5.
 
Due to copyright law, we are unable to distribute an electronic version of this reprint. The "download publication" button below will redirect you to where you can request a printed copy be sent to you once available.

2017 FDA Guidance: Many In Vitro DDI Evaluations Should Precede FIH Studies

Published:  06 December 2018

While the 2017 FDA DDI guidance contains many important changes, the earlier timing of drug-drug interaction studies is perhaps the most daunting. This is especially true for developers with drugs in the later clinical stages. Does this guidance mean sponsors are required to backtrack, and if so, how far? This article outlines the implications of these new timing requirements and best practices for negotiating them efficiently and effectively moving forward...

To GLP, or Not To GLP?

Published:  05 October 2018

Scott Hickman, Dr. Brian Ogilvie, Tim Patterson
In vitro drug interaction studies do not necessarily need to be performed under GLP conditions. To learn more — and probably save time and considerable money — read this article...

Challenges & Solutions in Today’s In Vitro Transporter Research

Published:  30 August 2018

Dr. Joanna Barbara

In vitro drug transport assays are performed throughout drug development and range from simple permeability screens to kinetic assessments in complex assay formats. Sometimes interpreting transporter assay results is straightforward, and sometimes applying the data to make smart decisions is challenging. Furthermore, the current regulatory landscape has presented new considerations for interpreting transporter assay results...

Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidances from Regulatory Agencies: Focus on CYP3A4 mRNA in vitro response thresholds, variability, and clinical relevance

Published:  29 June 2018

Jane R Kenny, Diane Ramsden, David B Buckley, Shannon Dallas, Conrad Fung, Michael Mohutsky, Heidi J Einolf, Liangfu Chen, Joshua G Dekeyser, Maria Fitzgerald, Theunis C Goosen, Y Amy Siu, Robert L Walsky, George Zhang, Donald Tweedie and Niresh Hariparsad
Drug Metabolism and Disposition June 29, 2018, dmd.118.081927; DOI: https://doi.org/10.1124/dmd.118.081927

Abstract
The IQ induction working group presents an assessment of best practice for data interpretation of in vitro induction, specifically, response thresholds, variability, application of controls and translation to clinical risk assessment with focus on CYP3A4 mRNA. Single concentration control data and Emax/EC50 data for prototypical CYP3A4 inducers were compiled from many human hepatocyte donors in different laboratories. Clinical CYP3A induction and in vitro data were gathered for 51 compounds, 16 of which were proprietary. A large degree of variability was observed in both the clinical and in vitro induction responses, yet analysis confirmed in vitro data are able to predict clinical induction risk. Following extensive examination of this large dataset, the following recommendations are proposed. (a) CYP induction should continue to be evaluated in three separate human donors in vitro. (b) In light of empirically divergent responses in rifampicin control and most test inducers, normalization of data to percent positive control appears to be of limited benefit. (c) Two-fold induction, with concentration dependence, is an acceptable threshold for positive identification of in vitro CYP3A4 mRNA induction. (d) To reduce the risk of false positives, in the absence of a concentration dependent response, induction o ≥ 2-fold should be observed in more than one donor to classify a compound as an in vitro inducer. (e) If qualifying a compound as negative for CYP3A4 mRNA induction, the magnitude of maximal rifampicin response in that donor should be o ≥10-fold. (f) Inclusion of a negative control adds no value beyond that of the vehicle control...

An assessment of the in vitro inhibition of cytochrome P450 enzymes (CYP), UDP-glucuronsyltransferases (UGT) and transporters by phosphodiester- or phosphorothioate-linked oligonucleotides

Published:  07 May 2018

Faraz Kazmi, Phyllis Yerino, Chase McCoy, Andrew Parkinson, David B Buckley and Brian W Ogilvie

Oligonucleotides represent an expanding class of pharmacotherapeutics in development for various indications. Typically, oligonucleotides are developed with phosphorothioate linkages for the improvement of biological stability; however limited data are available on the potential of these molecules to cause drug-drug interactions (DDIs). In the present study, two non therapeutic oligonucleotides with either phosphodiester (PD-GP and PD-Ac) or phosphorothioate (PT-GP and PT-Ac) linkages were evaluated in vitro for their potential to inhibit P450s and UGTs in both human liver microsomes (HLM) and cryopreserved human hepatocytes (CHH) and to inhibit select transporters in expression systems. PD-GP and PD-Ac had little-to-no inhibitory effect on any P450 or UGT enzymes in HLM and CHH except for PD-Ac in HLM for CYP2C19 (IC50 = 29 μM). Conversely, PT-GP and PT-Ac caused direct inhibition of almost all P450 and UGT enzymes, with CYP1A2 (IC50 values 0.8-4.2 μM), CYP2C8 (IC50 values 1.1-12 μM) and UGT1A1 (IC50 values 4.5-5.4 μM) inhibited to the greatest extent. There was evidence of possible time-dependent inhibition (TDI) of CYP enzymes with PT-GP and PT-Ac for CYP2B6, CYP2C8, CYP2C19, CYP2C9, CYP2D6 and CYP3A4/5; however, this TDI was reversible. In contrast to HLM, there was little-to-no direct CYP inhibition by any oligonucleotide in CHH (except for PD-Ac with CYP2C19 [IC50 = 36 μM] and TDI by PT-GP with CYP2C8), demonstrating test system-dependent outcomes. Inhibition was observed for the organic anion uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, and OCT2 (IC50 values 12-29 μM) but not OCT1 or the efflux transporters BCRP and P-gp by the phosphorothioate oligonucleotides.

Direct and cytokine‐mediated effects of albumin‐fused growth hormone, TV‐1106, on CYP enzyme expression in human hepatocytes in vitro

Published:  16 April 2018

Maciej Czerwiński, Immaculate Amunom, Victor Piryatinsky, Hussein Hallak, Yousif Sahly, Oren Bar‐Ilan, Paul Bolliger, Merav Bassan

Some biologics can modulate cytokines that may lead to changes in expression of drug‐metabolizing enzymes and cause drug‐drug interactions (DDI). DDI potential of TV‐1106—an albumin‐fused growth hormone (GH)—was investigated. In this study, human blood was exposed to recombinant human growth hormone (rhGH) or TV‐1106, followed by isolation of the plasma and its application to human hepatocytes. While the treatment of blood with rhGH increased multiple cytokines, treatment of blood with TV‐1106 had no effect on any of the nine cytokines tested. The interleukin (IL)‐6 concentration was higher in the rhGH then in the TV‐1106‐treated plasma (P< .05). While rhGH had little or no effect on CYP1A2 or CYP2C19 mRNA but increased CYP3A4 mRNA twofold, TV‐1106 had little or no effect on cytochrome P450 (CYP) mRNAs in hepatocytes. Although the plasma from rhGH‐treated blood lowered CYP1A2 activity, the TV‐1106 plasma had no effect on CYP activities. The CYP1A2 activity was lower in the rhGH‐ then in the TV‐1106‐plasma treated hepatocytes (P < .05). The results indicated that fusing GH with albumin made TV‐1106 an unlikely participant of CYP1A2, CYP2C19 or CYP3A4‐facilitated, direct or cytokine‐driven DDI.