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Do inhibitory metabolites impact DDI risk assessment? Analysis of in vitro and in vivo data from NDA reviews between 2013 and 2018.

Abstract

Evaluating the potential of new drugs and their metabolites to cause drug‐drug interactions (DDIs) is critical for understanding drug safety and efficacy. Although multiple analyses of proprietary metabolite testing data have been published, no systematic analyses of metabolite data collected according to current testing criteria have been conducted. To address this knowledge gap, 120 new molecular entities approved between 2013 and 2018 were reviewed. Comprehensive data on metabolite‐to‐parent area‐under‐the‐curve ratios (AUCM/AUCP), inhibitory potency of parent and metabolites, and clinical drug‐drug interactions (DDI) were collected. 64% of the metabolites quantified in vivo had AUCM/AUCP≥25% and 75% of these metabolites were tested for cytochrome P450 (CYP) inhibition in vitro, resulting in 15 metabolites with potential DDI risk identification. While 50% of the metabolites with AUCM/AUCP<25% were also tested in vitro, none of them showed meaningful CYP inhibition potential. The metabolite % plasma total radioactivity cutoff of ≥10% did not appear to add value to metabolite testing strategies. No relationship between metabolite versus parent drug polarity and inhibition potency was observed. Comparison of metabolite and parent maximum concentration (Cmax) divided by inhibition constant Ki values suggested that metabolites can contribute to in vivo DDIs and hence, quantitative prediction of clinical DDI magnitude may require both parent and metabolite data. This systematic analysis of metabolite data for newly approved drugs supports an AUCM/AUCP cutoff of ≥25% to warrant metabolite in vitro CYP screening to adequately characterize metabolite inhibitory DDI potential and support quantitative DDI predictions.

Watch our Comprehensive DIDB demonstration

We have recorded a one-hour long video tutorial suitable as a refresher training or to kick-start the use of DIDB. It starts by introducing the different lists available in the Resource Center of DIDB and then, it shows how to retrieve the human in vitro metabolism and transport information using preformulated queries. Finally it presents the in vivo datasets and how to retrieve clinical PK-based information from drug-drug interaction, food-effect, organ impairment and pharmacogenetics studies.

The video is available in DIDB Resource Center. Please note that you must be signed in to access.

In vivo Prediction Tool Available for Evaluation

We are pleased to provide access to an innovative online tool: DDPred, developed by the University of Lyon, France, that uses an in vivo static mechanistic model to predict PK-based DDIs with hundreds of substrates and inhibitors/inducers and evaluates the impact of polymorphism.

The link to this application will be available to all DIDB users during a 6-month evaluation. Please take the time to test it and to provide your feedback in the online survey. We value your feedback! Thank you.

New features! Drug Characteristics, Advanced Table Search, and more.

DIDB has been updated with the following new features:

  • Drug characteristics, e.g., substrate sensitivity, precipitant inhibition/induction potency, NTR, QT interval prolongation potential, are added into the drug monograph
  • A list of drugs with identified drug characteristics are presented in the Resource Center
  • “Advanced table search” function is added to filter the query results (in table view). See our updated video tutorial.

Feel free to contact us if you experience any issues or if you have any questions or suggestions. Your feedback is always greatly valued!

FDA Draft Guidance Gastric pH-Dependent Drug Interactions with Acid-Reducing Agents

The draft guidance newly released by FDA on “Evaluation go Gastric pH-Dependent Drug Interactions with Acid-Reducing Agents: Study Design, Data Analysis, and Clinical Implications” is now available in DIDB Resource Center. Please note that you must be signed in to access.

This draft guidance describes FDA’s recommendations regarding: (1) when clinical DDI studies with acid-reducing agents are needed; (2) the design of clinical DDI studies; (3) how to interpret study results; and (4) communicating findings in product labeling.

DIDB contains absorption-based drug interaction data. The study results are presented based on the underlying mechanism. For example, there are about 450 entries on pH-dependent drugs interactions in DIDB curated from literature and NDA reviews with detailed information about PK assessment results, study design, population, formulation, dosing, and safety results

New features! New filtering option on tables, in vitro transporter data in all drug queries, and more.

DIDB has been updated with the following new features:

  • Select filter added to Table view results
  • Query results presented in Table view first
  • Revised overall effect descriptions
  • Drug queries > Objects or Precipitants now support selecting multiple drugs (previous multiple objects/precipitants queries removed)
  • In vitro transport data added to all the Drug queries including Objects, Precipitants, and Object and precipitant Pair
  • In vitro transporter IC50 and Ki queries updated and % inhibition query added
  • In vivo transporter queries now take multiple elements
  • In vitro induction now has down regulation effect
  • FDA clinical index data updated

Feel free to contact us if you experience any issues or if you have any questions or suggestions. Your feedback is always greatly valued!

FDA Draft Guidance for Clinical Drug Interaction Studies with Combined Oral Contraceptives

The draft guidance newly released by FDA on “Clinical Drug Interaction Studies Combined with Oral Contraceptives” is now available in DIDB Resource Center. Please note that you must be signed in to access.

This draft guidance focuses on evaluating the DDI potential of an investigational new drug (i.e., perpetrator) on combined oral contraceptives  (COCs; i.e., victim) during drug development and determining how to communicate DDI study results and mitigation strategies to address potential risks associated with increased or decreased exposure of COCs in labeling.

In DIDB (as of Nov 2020), there are over 600 entries evaluating COCs as an object in dedicated clinical PK studies (including PGx data). On the other hand, nearly 200 entries were curated from clinical DDI studies where COCs serve as a precipitant.

FDA Guidance for Pharmacokinetics in Patients with Impaired Renal Function

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.