9.7 IMPACT OF METABOLISM INFORMATION ON NDA
FILING AND LABELING
FDA and ICH guidelines (see Chapter 7 for specific guidelines) require that
detailed studies be conducted to completely characterize the metabolic profile
of a drug. The list ofin vivoandin vitrostudies summarized in the sections
above aim to fulfill that purpose. The results generated from these studies are
included in the new drug application (NDA) where the data generated in
animal species and humans are integrated in the metabolism sections of the
nonclinical and the clinical pharmacology summaries. This integration of data
helps the reviewers in the regulatory agencies understand the comparative
metabolism across species and, specifically, review the data to see if animals are
adequately exposed to human metabolites. Reaction phenotyping studies in
conjunction with human ADME data, and CYP inhibition and induction studies,
provide information to the regulatory agencies about the potential for drug–drug
interaction and the metabolic liabilities, ifany, associated with the drug.
The results generated from the studies outlined above are also summarized in
the various sections of the product label. The key sections where drug
metabolism information and the recommendations based on the data appear
in the label are (1) Pharmacokineticswhere the overall ADME properties of
the drug in humans is summarized based on pharmacokinetic and radiolabeled
human studies, (2) Drugdrug interactionswhere the potential interactions of
the drug as a substrate, inhibitor or inducer of the CYP enzymes are summarized
based on key clinical drug–drug interaction (DDI) data as well asin vitroreaction
phenotyping and CYP inhibition and induction data and, (3) Precautions
where information is provided for interactions with different classes of drugs and
how it can be clinically managed. Both the drug–drug interaction and precaution
sections of the label provide the prescribing physicians with the relevant
information to either adjust the dose or avoid prescribing the medicine when the
patients are taking concomitant interacting medications.
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