Contribution of metabolites to P450 inhibition-based drug-drug interactions: scholarship from the drug metabolism leadership group of the innovation and quality consortium metabolite group.

Recent European Medicines Agency (final) and US Food and Drug Administration (draft) drug interaction guidances proposed that human circulating metabolites should be investigated in vitro for their drug-drug interaction (DDI) potential if present at ≥ 25% of the parent area under the time-concentration curve (AUC) (US Food and Drug Administration) or ≥ 25% of the parent and ≥ 10% of the total drug-related AUC (European Medicines Agency). To examine the application of these regulatory recommendations, a group of scientists, representing 18 pharmaceutical companies of the Drug Metabolism Leadership Group of the Innovation and Quality Consortium, conducted a scholarship to assess the risk of contributions by metabolites to cytochrome P450 (P450) inhibition-based DDIs. The group assessed the risk of having a metabolite as the sole contributor to DDI based on literature data and analysis of the 137 most frequently prescribed drugs, defined structural alerts associated with P450 inhibition/inactivation by metabolites, and analyzed current approaches to trigger in vitro DDI studies for metabolites.

Exploring the feasibility of using the DBS technique for metabolite radioprofiling.

Background: The dried blood spots (DBS) technique has been actively evaluated as plasma replacement for monitoring drug exposure to support drug development in preclinical/clinical pharmacokinetic and toxicokinetic studies. Plasma samples from some of these studies are typically used for metabolite profiling and identification and for determination of disproportionate metabolites between safety species and humans to address metabolites in safety testing issues. The objectives of this study were to explore the feasibility of using the DBS technique for a metabolism study and to compare metabolite radioprofiles between DBS, plasma and whole blood samples.

Estimating mass balance for inhaled drugs in humans: an example with a VLA-4 antagonist, IVL745.

IVL745 is an inhaled VLA-4 antagonist developed for the treatment of asthma. Following inhalation (Inh), a fraction of the drug is deposited in the oropharynx, and the rest is deposited in the lungs. For inhaled drugs, it is technically and ethically difficult to formulate and administer radiolabeled drugs.