The Evaluation of Interactions Between Multiple Intrinsic and Extrinsic Factors Reported in Labeling for FDA-Approved Drugs.

Abstract

A critical aspect of drug development is evaluating pharmacokinetics (PK) and pharmacodynamics to assess how intrinsic (e.g., age, sex, comorbidities, and genomics) and extrinsic (e.g., drug-drug interactions [DDIs] and food interaction) factors influence drug exposure and response. These aspects guide dose selection and inform drug labeling by accounting for interindividual variability to ensure safe and effective use across complex patient populations. However, identifying the relationship of co-occurring factors, resembling complex patient populations, remains challenging. Herein, we analyzed drug labeling for therapeutic products approved by the Center of Drug Evaluation and Research at the US Food and Drug Administration from 2019 to 2023 to understand if intrinsic and extrinsic factors are considered simultaneously and how these factors influence prescribing recommendations. We characterized factors including pharmacogenomics (PGx), renal and hepatic function, age, pregnancy, body weight, comorbidities, and DDIs. Among 227 drug labelings, 93% independently assessed more than one factor and 2.6% evaluated the combined influence of two factors. Most drug labelings focused on single factors, with PK DDIs (70.0%), renal impairment (74.4%), and age (78.9%) frequently assessed. In rare disease indications, no significant differences in factor assessment frequency were observed. Of the six drug labelings that address simultaneously occurring factors, four addressed the interaction between PGx and PK DDIs. This analysis highlights a gap in evaluating co-occurring intrinsic and extrinsic factors in drug labeling, underscoring the need for integrated approaches during drug development to better guide clinical decision making for complex patient populations.