PII-117 - DRUG DEVELOPMENT CONSIDERATIONS FOR DRUG-DRUG INTERACTION STUDIES WITH FLUCONAZOLE AS A SIMULTANEOUS INHIBITOR OF MULTIPLE METABOLIC ENZYMES.

J. Huynh¹, Y. Pithavala², K. Kowalski³; ¹UCSD, La Jolla, CA, USA, ²Pfizer, Inc., San Diego, CA, USA, ³Pfizer, La Jolla, CA, USA.

Background: Unlike other azoles, fluconazole inhibits multiple enzymes (strong CYP2C19 inhibitor and moderate inhibitor of CYP2C9 and CYP3A4). For drugs metabolized by multiple isozymes, coadministration with fluconazole may lead to elevated substrate exposures compared to a single CYP inhibitor alone. The objective of this work was to query published literature to characterize the magnitude of change in substrate exposures when given with fluconazole in clinical DDI studies and to assess the corresponding labeled dose adjustment for the substrates.

Methods: Literature search was conducted using Pubmed and Certara’s Drug Interaction Database for clinical fluconazole DDI inhibition studies published 2000-2024. The magnitude of the interaction quantified by change in AUC for substrate drugs metabolized by CYP2C19, 2C9, or 3A4 when co-administered with fluconazole versus alone was assessed.

Results: Since 2000, 52 fluconazole DDI studies have been published, with a greater incidence of these publications for more recently approved drugs. Substrates metabolized to any extent by CYP2C19, 2C9, and 3A4 showed on average a 101.8% (95% CI, 35.2 – 168.3) increase in substrate AUC with fluconazole compared to 88.6% (37.1 – 140.0) for substrates metabolized by CYP3A4 alone. In line with expectations, substrates with a labeled dose adjustment recommendation had a statistically significant (p < 0.05) higher increase in AUC (92%, inter-quartile range 53 – 178) when co-administered with fluconazole compared to those without a dose adjustment recommendation (32.5%, 15 – 83).

Conclusion: Interpretation of the increase in substrate AUC by fluconazole via inhibition of CYP2C19, CYP2C9, and CYP3A4 (either 1 isozyme alone, or in combination) is challenging because the fraction of metabolism (fm) for each isozyme is not always known. Overall, to characterize the maximal increase in plasma exposure for drugs in development that are metabolized by multiple enzymes (CYP3A, CYP2C9, CYP2C19) the impact of dual metabolic inhibition needs to be considered. This can be addressed by a clinical DDI study with fluconazole or by validated PBPK models.