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In Vitro, In Vivo Drug Interaction Studies for NDAs and BLAs

Released in 2012, the Guidance, “Clinical Drug Interaction Studies – Study Design, Data Analysis, and Clinical Implications,” provides recommendations regarding in vitro, in vivo studies of drug metabolism, drug transport, and drug-drug or drug-therapeutic protein interactions. The guidance is aimed at sponsors of new drug applications (NDAs) and biologics license applications (BLAs) regulated by CDER (Center for Drug Evaluation and Research).

General Overview

The overall objective of drug interaction studies for a new drug is to determine whether potential interactions between the investigational drug and other drugs exist and, if so, whether the potential for such interactions indicates the need for dosage adjustments, additional therapeutic monitoring, a contraindication to concomitant use, or other measures to mitigate risk.

Drug development should include 1) identification of the principal routes of elimination, 2) quantification of the contribution by enzymes and transporters to drug disposition, and 3) characterization of the mechanisms of drug-drug-interactions (DDI). Early PK studies, combined with in vitro studies, can be used to refine physiologically-based pharmacokinetic (PBPK) models to inform the need for and design of future DDI studies. The guidance states that, “In many cases, negative findings from early in vitro and clinical studies eliminate the need for later clinical investigations of DDI.”

Drug interactions to consider for small molecule drugs include evaluation of a new drug’s potential to affect other drugs and the potential for the new drug to be affected by other drugs through metabolism-based interactions, transporter-based interactions, or combinations of multiple interaction mechanisms.  Therapeutic proteins (TPs) tend not to utilize metabolizing enzymes and transporters for clearance to the same extent as small molecule drugs and are considered to have a lower potential for drug interaction overall; considerations for TPs generally focus on the class (e.g., cytokines are known to impact CYPs, immunosuppression by methotrexate can impact TPs), and intended use (e.g., combination therapy).  General strategies, which will be covered in subsequent posts, include in vitro studies, in vivo studies, and using a population pharmacokinetic (popPK) approach to assess drug-drug interactions.

What’s on a Label?

The label should include clinically relevant information about metabolic and transport pathways, metabolites, PK or PD interactions and clinical implications of genetic polymorphisms. Clinical implications should include dosage adjustments and monitoring recommendations.

The DRUG INTERACTIONS section of labeling should include the clinical implications of significant interactions with other drugs and drug classes, food and dietary supplements, interference with lab tests and instruction on management of these interactions.  The label should list the most relevant interaction first and may include the data source, particularly if a mix of study results and predictive modelling are described. Dose adjustments should be summarized here and detailed elsewhere (DOSAGE AND ADMINISTRATION).

The PHARMACOKINETICS subsection of the CLINICAL PHARMACOLOGY section is typically organized into multiple subheadings (e.g., absorption, distribution, metabolism, excretion, pharmacokinetics in specific populations, and drug interactions) and should contain descriptive information related to mechanisms of drug interactions and the details of the interaction studies.  If the drug is a substrate for metabolizing enzymes or transporters, details in ‘Metabolism’ should include the metabolic pathway, relevant metabolites, specific enzymes and a brief summary of relevant genetic polymorphisms (further detailed in the PHARMACOGENOMICS subsection).  Forest plots are recommended as “a useful tool for presenting changes in pharmacokinetic exposure measures caused by various intrinsic and extrinsic factors, such as drug interactions, hepatic impairment, and renal impairment” and should display the fold-change in key PK measures (e.g., geometric mean AUC) along with 90% confidence intervals.

When the safe and effective use of the drug is impacted by drug interactions, the information may be distributed among several other labeling sections:

  • DOSAGE AND ADMINISTRATION – including dosage adjustments and the timing of doses relative to other drugs
  • CONTRAINDICATIONS – circumstances in which other drugs should not be co-administered because the risks outweigh the benefits
  • WARNINGS AND PRECAUTIONS – known or predicted drug interactions with serious or clinically significant outcomes
  • PATIENT COUNSELING INFORMATION – information necessary for patients to use the drug safely and effectively

Learn more about In Vitro, and In Vivo  Drug Interaction Studies for NDAs and BLAs
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