Evaluating the Evidence for CYP2C19 Inhibitor Classifications: A Scoping Review.

Area of Science:

• Pharmacology
• Drug Metabolism
• Clinical Pharmacy

Background:

• The Food and Drug Administration (FDA) and Flockhart tables are key resources for identifying cytochrome P450 19 (CYP2C19) inhibitors.
• Accurate classification of CYP2C19 inhibitors is crucial for assessing drug phenoconversion and managing potential drug-drug interactions.

Purpose of the Study:

• To evaluate the agreement between CYP2C19 inhibitor classifications in the FDA and Flockhart tables and classifications derived from primary literature pharmacokinetic data.
• To identify discrepancies and propose revisions to enhance the clinical utility of these inhibitor reference tables.

Main Methods:

• A scoping review of PubMed, drug labels, and the Drug Interactions Database (DIDB®) was performed up to April 2024.
• Inhibitor-substrate pairs were identified, and their classifications were determined based on literature-reported pharmacokinetic data.
• Concordance between literature-derived classifications and those listed in the FDA and Flockhart tables was assessed.

Main Results:

• Of 90 inhibitor-substrate pairs, 66% involved sensitive substrates. Concordance with literature data was 36% for FDA listings and 45% for Flockhart listings.
• Concordance varied based on CYP2C19 phenotype, with higher agreement observed in normal metabolizers (42% FDA, 50% Flockhart).
• Factors such as steady-state status and dosing regimens also influenced classification concordance.

Conclusions:

• Significant discrepancies exist between established CYP2C19 inhibitor tables and real-world pharmacokinetic data.
• Specific recommendations include upgrading fluoxetine and fluconazole to strong inhibitors and downgrading omeprazole/esomeprazole to weak inhibitors in the Flockhart Table™.
• Inclusion of dose-dependent inhibition footnotes for fluvoxamine and fluconazole in both tables is advised to improve accuracy and clinical applicability.