The June Newsletter is now available. You can see this and past newsletters in the DIDB Resource Center. Please note that you must be signed in to access.
Do not hesitate to contact us with comments or suggestions.
News
Lists of Sensitive Substrates, Inhibitors and Inducers updated
The lists of sensitive substrates, inhibitors, and inducers, including the file combining all lists, have been updated and are available in the Resource Center.
As always, feel free to contact us if you have any questions or comments.
All 2019 NDAs and BLAs now fully curated into DIDB
Data entry for drug therapies approved by FDA in 2019 is now complete. Among the 48 drugs (38 NDAs and 10 BLAs) approved last year, 39 (33 NDAs and 6 BLAs) have relevant in vitro and clinical findings related to DDI, PGx, food effect, and/or organ impairment. Drug monographs are also available, summarizing key DDI results, QT, and PK information.
The full list of NDA/BLAs entered in DIDB can be found at https://didb.druginteractionsolutions.org/resources/all-ndas/
Do not hesitate to contact us with comments or suggestions.
New features! Full text search, food effect studies, and more.
DIDB has been updated with the following new features:
- New full text search of all our citations, monographs, and resources; that’s 23,000 pages.
- New in vivo queries to retrieve food effect studies. Find queries in object query in PK section and AUC/CL change query. Food effect badge added to citations throughout DIDB when the citation contains a food effect study.
- New all monographs and all QT summaries pages.
- Better organized home and all queries pages. Menu as been changed to reflect these.
- The find all studies for a compound query is now lighting fast.
- All queries in the PK section now take multiple compounds.
- Semantic Scholar links have been added when citation exists in Semantic Scholar (an Allen Institute for AI project).
Feel free to contact us at didbase@uw.edu if you experience any issues or if you have any questions or suggestions. Your feedback is always greatly valued!
Finalized FDA DDI guidances now available in the DIDB Resource Center
New finalized In Vitro & Clinical Drug Interaction Studies FDA guidances (January 2020) are now available in the DIDB Resource Center. Please note that you must be signed in to access.
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
Published online 2020 Jan 25
- PMID: 31981398
- doi: 10.1111/cts.12750
- Semantic Scholar
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
Published online 2019 Aug 29
- PMID: 31468718
- doi: 10.1111/cts.12691
- Semantic Scholar
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.