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Enzyme- and Transporter-Mediated Clinical Drug Interactions with Drugs by the U.S. Food and Drug Administration in 2021: What Can be Learned from New Drug applications Reviews?

Presented at the ISSX/MDO Meeting, September 2022
Jingjing Yu, Yan Wang, and Isabelle Ragueneau-Majlessi

2022 ISSX Poster Presentation – 2021 NDA Reviews

Abstract

 The mechanistic evaluation of enzyme- and transporter-based drug-drug interactions (DDIs) during drug development is critical to support management strategies in the clinic.

The objectives of the study were to review pharmacokinetic-based clinical DDI data available in the new drug application (NDA) reviews for drugs approved by the FDA in 2021, and to understand the main mechanisms that mediate interactions resulting in label recommendations. 

 |  New features

New features! Drug Characteristics queries expanded, and Invite a colleague to use DIDB

Drug characteristics queries are expanded from AUC-CL change queries to Drug queries. Two drug queries are now enabling users to search using object or precipitant characteristics: 

  • the Drug queries with Objects
  • the Drug queries with Precipitants

Invite a colleague to register to access DIDB. With this feature most of you (some restrictions apply based on the license type) can now invite a colleague from your company to register to access DIDB. Anyone working in preclinical DMPK, Clinical Pharmacology, Safety, Medical, and Regulatory Affairs can benefit from using DIDB.

When you are signed in DIDB, you can use the “invite a colleague” green button located on the right side of each of the DIDB pages, alongside the “contact us” blue button.

As always, feel free to contact us if you have any questions or comments. Your feedback is critical to make the most of the DIDB content and functionalities!

 |  News

Data Curation and Entry in DIDB – July Summary

In July, we added 73 citations in DIDB, including 35 in vitro (with 21 articles published in July 2022) and 38 in vivo articles (with 33 articles published in July 2022).

Two recently approved NDAs were also added: mavacamten (CAMZYOS), vutrisiran (AMVUTTRA).

Of note, all new drugs approved by the FDA from January to July this year (N = 16) have been curated in DIDB, and a DDI drug monograph for each drug was created.

You can check the citations that are recently published and entered in DIDB and all the NDAs/BLAs in DIDB.

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

 |  Events

UW Drug Interaction Database team to attend the ISSX/MDO Meeting

The UW Drug Interaction Database team will be attending the ISSX/MDO Meeting in Seattle, WA on Sept 11-14, 2022. In addition to our booth #24, we hope to meet you at our poster #P56:

  • “Enzyme- and transporter-mediated clinical drug interactions with drugs approved by the U.S Food and Drug Administration in 2021: What can be learned from New Drug Application reviews?”; presented by Dr. Jingjing Yu on Sept 13 in the Fifth Avenue Room.
 |  News

DDI Marker Studies Knowledgebase – quarterly update

The DDI Marker Studies Knowledgebase (replacing the previous combined and individual lists of CYP/P-gp substrates and perpetrators) has been updated in July 2022, and is available in the DIDB Resource Center.

In addition to substrates, inhibitors and inducers of CYPs and transporters, the Knowledgebase provides useful information on the compounds therapeutic class, clinical recommended dosage, pharmacokinetics (e.g. dose proportionality accumulation ratio, time to steady-state), QT prolongation, and NTI characteristics.

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

 |  News

Data Curation and Entry in DIDB – June Summary

In June, we added 76 citations in DIDB, including 31 in vitro (with 12 articles published in June 2022) and 45 in vivo articles (with 31 articles published in June 2022).

Four recently approved NDAs were also added: vonoprazan and amoxicillin and clarithromycin (VOQUEZNA TRIPLE PAK), oteseconazole (VIVJOA), tapinarof (VTAMA), tirzepatide (MOUNJARO)

You can check the citations that are recently published and entered in DIDB and all the NDAs/BLAs in DIDB.

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

 |  News

Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics – Guidance for Industry

The draft guideline published by the FDA on Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics is now available in DIDB Resource Center. Please note that you must be signed in to access.

This guideline provides recommendations for certain evaluations including pharmacokinetics, pharmacodynamic, and safety assessments during oligonucleotide therapeutic development.

A dozen of oligonucleotide drugs have been approved by the FDA and are included in DIDB. You will find data for evaluations recommended by the FDA guidance, e.g., QT interval prolongation, organ impairment, metabolism and transport DDI.

 |  News

Assessing the Effects of Food on Drugs in INDs and NDAs – Clinical Pharmacology Considerations

The final guideline published by the FDA on Assessing the Effects of Food on Drugs in INDs and NDAs is now available in DIDB Resource Center. Please note that you must be signed in to access.

This guidance revises and replaces part of the 2002 FDA guidance entitled Food-Effect Bioavailability and Fed Bioequivalence Studies (December 2002). 

This guideline provides recommendations to sponsors planning to conduct food-effect (FE) studies for orally administrated drug products under INDs, to support NDAs, and supplements to these applications for drugs being developed under section 505 of the Federal Food, Drug, and Cosmetic Act. (21 U.S.C 335).

Note that clinical food effects data are curated by our DIDB Editorial Team. They are entered in DIDB as single drug PK studies with no precipitant. Changes in AUC, CL, and plasma concentrations are calculated for the fed state versus the control fasted state.