The September 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.
The guidance newly released by FDA on “Pharmacokinetics in Patients with Impaired Renal Function — Study Design, Data Analysis, and Impact on Dosing and Labeling” is now available in DIDB Resource Center. Please note that you must be signed in to access.
For your information, DIDB contains study results from organ impairment studies following the recommendations in the FDA guidances on impaired renal function and on impaired hepatic function. As such study design, population, degree of organ impairment, drug dosing, PK, PD, and safety results are extracted from the literature and NDAs/BLAs reviews and entered in DIDB.
The draft guidance newly released by FDA on “Drug-Drug Interaction Assessment of Therapeutics Proteins” is now available in DIDB Resource Center. Please note that you must be signed in to access.
For your information, in addition to small molecules, DIDB also contains drug-drug interaction data for therapeutic proteins extracted from literature and FDA biological license applications (BLAs).
New drug application reviews contain critical drug interaction study results with newly approved drugs tested both as victims and as perpetrators of drug-drug interactions (DDIs). Pharmacokinetic-based DDI data for drugs approved by the US Food and Drug Administration in 2013–2017 (N = 137) were analyzed using the University of Washington Drug Interaction Database. For the largest metabolism- and transporter-based drug interactions, defined as a change in exposure ≥ 5-fold in victim drugs, the mechanisms and clinical relevance were characterized. Consistent with the major role of CYP3A in drug disposition, CYP3A inhibition and induction explained a majority of the observed interactions (new drugs as victims or as perpetrators). However, transporter-mediated interactions were also prevalent, with OATP1B1/1B3 playing a significant role. As victims, 17 and 4 new molecular entities (NMEs) were identified to be sensitive substrates of enzymes and transporters, respectively. When considered as perpetrators, three drugs showed strong inhibition of CYP3A, one was a strong CYP3A inducer, and two showed strong inhibition of transporters (OATP1B1/1B3 and/or BCRP). All DDIs with AUC changes ≥ 5-fold had labeling recommendations in their respective drug labels, contraindicating or limiting the coadministration with known substrates or perpetrators of the enzyme/transporter involved. The majority of sensitive substrates or strong inhibitors were oncology and antiviral treatments, suggesting a significant risk of DDIs in these patient populations for whom therapeutic management is already complex due to poly-therapy. Pharmacogenetic studies and physiologically based pharmacokinetic models were commonly used to assess the drug interaction potential in specific populations and clinical scenarios. Finally, absorption-based DDIs were evaluated in approximately 30% of drug applications, and 14 NMEs had label recommendations based on the results.
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.
In our new support page, you will find FAQs, brochures, and videos which will take you inside the DIDB to view its content, features and functionality.
For first-time DIDB users and refresher training, you are encouraged to review our updated detailed tutorials on how to use the different in vitro and in vivo queries.
Organic anion-transporting polypeptides (OATPs) 1B1 and 1B3 are the primary hepatic transporters responsible for uptake of drugs into the liver and, as such, an area of growing research focus. Currently, evaluation of these transporters as potential mediators of drug-drug interactions (DDIs) is recommended by regulatory agencies worldwide during the drug development process. Despite the growing focus on OATP1B1/1B3 as mediators of DDIs, only 2 drugs are recommended as index inhibitors for use in clinical studies, single-dose rifampin and cyclosporine, each with limitations for the utility of the resulting data. In this study a thorough analysis of the available in vitro and clinical data was conducted to identify drugs that are clinically relevant inhibitors of OATP1B1/1B3 and, from those, to select any novel index inhibitors. A total of 13 drugs and 16 combination products were identified as clinical inhibitors of OATP1B1/1B3, showing significant changes in exposure for sensitive substrates of the transporters, with strong supporting in vitro evidence. Although none of the identified inhibitors qualified as index inhibitors, this study confirmed the utility of cyclosporine and single-dose rifampin as index inhibitors to evaluate the effect of broad, multiple-pathway inhibition and more selective OATP1B1/1B3 inhibition, respectively.
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.
DIDB has been updated with the following new features:
Feel free to contact us at email@example.com if you experience any issues or if you have any questions or suggestions. Your feedback is always greatly valued!
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.