News

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.

Organic Anion Transporting Polypeptide 2B1 – More Than a Glass-Full of Drug Interactions

Abstract

The importance of uptake transporters in determining drug disposition is increasingly appreciated. While the focus of regulatory agencies worldwide has been on the hepatic organic anion transporting polypeptides (OATPs)-1B1 and-1B3, there is another isoform of the OATP sub-family, OATP2B1, which should be considered equally relevant. Unlike the other members of the OATP sub-family, OATP2B1 is expressed in multiple organs in humans, including in the intestine and the liver. Similar to other OATPs, OATP2B1 mediates the hepatic and intestinal uptake of many drugs and endogenous compounds. The importance of OATP2B1 in the disposition of many drugs is highlighted by the growing recognition of its role in significant in vivo drug-drug or food-drug interactions. The dramatic changes in drug exposure attributable to inhibition of OATP2B1 highlight the importance of developing a better understanding of the clinical role of OATP2B1. This review aims to provide a thorough summary of the current understanding of the pharmacogenetics, regulation, expression and abundance of OATP2B1 in humans, as well as its clinical relevance in drug-drug and food-drug interactions.

Upcoming release of new features on April 6, 2019!

The DIDB Team will release new features on Saturday April 6, 2019. The release includes the following improvements:

  • Revised home page with a new “Latest NDAs entered” section.
  • Added number of entries (studies) to standard citation info.
  • Added new monograph page for all compounds.
    • This new monograph page combines the previously separate PK summary, QT summary, and monograph into a single page.
    • What was formerly known as “Monograph” is now “DDI summary” and has been renamed throughout application.
    • New monograph page also aggregates some other additional information on each compound such as DIDB defined compound relationships, other properties from DIDB, and some selected external resources.
    • Every compound has a monograph page, but many compounds may not have a DDI, PK, or QT summary, so there may be very little information presented.
  • In Resource Center, added listings of all compounds in each therapeutic class, including DDI risk information.  This new therapeutic class information is a replacement for the DDI risk information which was presented in the Disease section.   The entire Disease section has been removed.
  • In Resource Center, added two new listings – all compounds with DDI Summaries and all compounds with PK Profiles.
  • Removed pdf product labels and replaced with link to Drugs@FDA when an NDA is related to the drug.

Do not hesitate to contact us at didbase@uw.edu if you have any feedback or questions!

Drug-Drug Interactions of Infectious Disease Treatments in Low-Income Countries: A Neglected Topic?

Clin Pharmacol Ther. 2019 Jun; 105(6); 1378-1385.
Published online 2019 Feb 16

Abstract

Despite recent advances in recognizing and reducing the risk of drug-drug interactions (DDIs) in developed countries, there are still significant challenges in managing DDIs in low-income countries (LICs) worldwide. In the treatment of major infectious diseases in these regions, multiple factors contribute to ineffective management of DDIs that lead to loss of efficacy or increased risk of adverse events to patients. Some of these difficulties, however, can be overcome. This review aims to evaluate the inherent complexities of DDI management in LICs from pharmacological standpoints and illustrate the unique barriers to effective management of DDIs, such as the challenges of co-infection and treatment settings. A better understanding of comprehensive drug-related properties, population-specific attributes, such as physiological changes associated with infectious diseases, and the use of modeling and simulation techniques are discussed, as they can facilitate the implementation of optimal treatments for infectious diseases at the individual patient level.

Mechanisms and Clinical Significance of Pharmacokinetic-Based Drug-Drug Interactions With Drugs Approved by the U.S. Food and Drug Administration in 2017

Abstract

Pharmacokinetic-based drug-drug interaction (DDI) data for drugs approved by the U.S. Food and Drug Administration in 2017 (N = 34) were analyzed using the University of Washington Drug Interaction Database. The mechanisms and clinical relevance of these interactions were characterized based on information from new drug application reviews. CYP3A inhibition and induction explained most of the observed drug interactions (new drugs as victims or as perpetrators), and transporters mediated about half of all DDIs, alone or with enzymes. Organic anion transporting polypeptide (OATP)1B1/1B3 played a significant role, mediating more than half of the drug interactions with area under the time-plasma curve (AUC) changes ≥5-fold. As victims, five new drugs were identified as sensitive substrates: abemeciclib, midostaurin, and neratinib for CYP3A and glecaprevir and voxilaprevir for OATP1B1/1B3. As perpetrators, three drugs were considered strong inhibitors: ribociclib for CYP3A, glecaprevir/pibrentasvir for OATP1B1/1B3, and sofosbuvir/velpatasvir/voxilaprevir for OATP1B1/1B3 and breast cancer resistance protein. No strong inducer of enzymes or transporters was identified. DDIs with AUC changes ≥5-fold and almost all DDIs with AUC changes 2- to 5-fold had dose recommendations in their respective drug labels. A small fraction of DDIs with exposure changes <2-fold had a labeling impact, mostly related to drugs with narrow therapeutic indices. As with drugs approved in recent years, all drugs found to be sensitive substrates or strong inhibitors of enzymes or transporters were among oncology or antiviral treatments, suggesting a serious risk of DDIs in these patient populations for whom effective therapy is already complex because of polytherapy.