News

In Vitro-to-In Vivo Extrapolation of Transporter Inhibition Data for Drugs Approved by the US Food and Drug Administration in 2018

Clin Transl Sci.
Published online 2020 Jan 25

Abstract

A systematic analysis of the inhibition transporter data available in New Drug Applications of drugs approved by the US Food and Drug Administration (FDA) in 2018 (N = 42) was performed. In vitro‐to‐in vivo predictions using basic models were available for the nine transporters currently recommended for evaluation. Overall, 29 parents and 16 metabolites showed in vitro inhibition of at least one transporter, with the largest number of drugs found to be inhibitors of P‐gp followed by BCRP. The most represented therapeutic areas were oncology drugs and anti‐infective agents, each comprising 31%. Among drugs with prediction values greater than the FDA recommended cutoffs and further evaluated in vivo, 56% showed positive clinical interactions (area under the concentration‐time curve ratio (AUCRs) ≥ 1.25). Although all the observed or simulated inhibitions were weak (AUCRs < 2), seven of the nine interactions (involving five drugs) resulted in labeling recommendations. Interestingly, more than half of the drugs with predictions greater than the cutoffs had no further evaluations, highlighting that current basic models represent a useful, simple first step to evaluate the clinical relevance of in vitro findings, but that multiple other factors are considered when deciding the need for clinical studies. Four drugs had prediction values less than the cutoffs but had clinical evaluations or physiologically‐based pharmacokinetic simulations available. Consistent with the predictions, all of them were confirmed not to inhibit these transporters in vivo (AUCRs of 0.94–1.09). Overall, based on the clinical evaluations available, drugs approved in 2018 were found to have a relatively limited impact on drug transporters, with all victim AUCRs < 2.

Lists of Sensitive Substrates, Inhibitors and Inducers updated + New Combined List

The lists of sensitive substrates, inhibitors, and inducers have been updated and are available in the Resource Center.

Note that we are working on improving the consistency of the presentation so you may notice small changes in some of the drug names or therapeutic classes. Also, for the same reason, we are now presenting all changes in exposure as AUC ratios.

Finally, you will find a new Excel file, combining all the information, so that you can search easily using any of the headings (drug name, therapeutic class, CYP…). Any feedback on this new combined file is welcome!

As always, feel free to contact us if you have any questions or comments.

We are now druginteractionsolutions.org

We have changed our domain to match our new name of UW Drug Interaction Solutions. We feel this name change better reflects our expanding activities and offerings.

All old bookmarks and links will still work, they will be redirected to the same page on our new domain.

If you have any questions or issues please contact us.

As always, don’t forget to check us out and follow us on Linked.

New queries available for beta testing

New queries are now available for beta testing under “FDA Marker Queries”. They allow you to search for in vitro and clinical data for inhibitors of CYP markers, and, in a second step from the query results page, view clinical concentrations of each inhibitor.

We are looking forward to your feedback!

Variability in In Vitro OATP1B1/1B3 Inhibition Data: Impact of Incubation Conditions on Variability and Subsequent Drug Interaction Predictions

Clin Transl Sci. 2020 Jan; 13(1): 47–52.
Published online 2019 Aug 29

Abstract

As the research into the organic anion transporting polypeptides (OATPs) continues to grow, it is important to ensure that the data generated are accurate and reproducible. In the in vitro evaluation of OATP1B1/1B3 inhibition, there are many variables that can contribute to variability in the resulting inhibition constants, which can then, in turn, contribute to variable results when clinical predictions (R-values) are performed. Currently, the only experimental condition recommended by the US Food and Drug Administration (FDA) is the inclusion of a pre-incubation period.1 To identify other potential sources of variability, a descriptive analysis of available in vitro inhibition data was completed. For each of the 21 substrate/inhibitor pairs evaluated, cell type and pre-incubation were found to have the greatest effect on half-maximal inhibitory concentration (IC50 ) variability. Indeed, when only HEK293 cells and co-incubation conditions were included, the observed variability for the entire data set (highest IC50 /lowest) was reduced from 12.4 to 5.2. The choice of probe substrate used in the study also had a significant effect on inhibitor constant variability. Interestingly, despite the broad range of inhibitory constants identified, these two factors showed little effect on the calculated R-values relative to the FDA evaluation cutoff of 1.1 triggering a clinical evaluation for the inhibitors evaluated. However, because of the small data set available, further research is needed to confirm these preliminary results and define best practice for the study of OATPs.

ISSX Posters available in the Resource Center

The posters presented at the 12th International ISSX Meeting in Portland by the DIDB team are now available in the Resource Center’s DIDB Team’s Most Recent Communications section:

  • “Main mechanisms of PK DDIs triggering label recommendations for drugs approved by FDA in 2018” (Dr. Jingjing Yu et al.)
  • “Variability of OATP1B1/1B3 in vitro inhibition constants and the resulting impact on clinical evaluation” (Dr. Savannah McFeely et al.)

Variability of OATP1B1/1B3 in vitro inhibition constants and the resulting impact on clinical evaluation

Presented at ISSX conference, June 2019, Portland, OR, USA
Savannah J. McFeely, Yu, Tasha K. Ritchie, and Isabelle Ragueneau-Majlessi

2019 ISSX Poster Presentation – Evaluation of OATP1B1/3 In Vitro Inhibition

Abstract

The effect of inhibition of the organic anion transporting polypeptides (OATP) 1B1 and 1B3 has continued to grow in clinical significance and recognition. In the last five years, a signification portion of newly approved drugs in the US have been shown to be inhibitors of OATP1B1 and/or OATP1B3 in vitro. For this reason, it is critical to understand the effect of experimental variability on drug interaction predictions and how it impacts the decision for a clinical evaluation.

Main mechanisms of pharmacokinetic drug-drug interactions triggering label recommendations for drugs approved by the Food and Drug Administration in 2018

Presented at ISSX conference, June 2019, Portland, OR, USA
Jingjing Yu, Ichiko Petrie, and Isabelle Ragueneau-Majlessi

2019 ISSX Poster Presentation – 2018 NDA Clinical DDI Review

Abstract

The aim of the present work was to review pharmacokinetic drug-drug interaction (DDI) data available in New Drug Applications (NDAs) for drugs approved by the US Food and Drug Administration in 2018 and analyze the mechanisms mediating interactions that triggered label recommendations.

Update of our website to come soon

We will be updating the homepage and the public content of our website over the coming few weeks, with an early version released next week. Our new program name, UW Drug Interaction Solutions, reflects our expanding activities and offerings. You can view/download a new brochure and technical flyers on our redesigned homepage.

Note that once you have logged in, the web pages dedicated to subscribers have not changed and you will find all the queries, functions, and editorial content you are used to.

We have also launched a LinkedIn page for UW Drug Interaction Solutions where you can find the most recent news and events regarding the program.

UW Drug Interaction Database team to attend the 12th International ISSX Meeting

The UW Drug Interaction Database team will be attending the 12th International ISSX Meeting in Portland next week. In addition to our booth #316, we hope to meet you at one of our posters:

  • “Main mechanisms of PK DDIs triggering label recommendations for drugs approved by FDA in 2018”; presented by Dr. Jingjing Yu on July 29 at 11am
  • “Variability of OATP1B1/1B3 in vitro inhibition constants and the resulting impact on clinical evaluation”; presented by Dr. Savannah McFeely on July 31st at 12:30pm.