Strong Pharmacokinetic Drug-Drug Interactions With Drugs Approved by the US Food and Drug Administration in 2021: Mechanisms and Clinical Implications
Jingjing Yu 1, Yan Wang 2, Isabelle Ragueneau-Majlessi 2
Purpose: This analysis aimed to identify all strong drug-drug interactions (DDIs) associated with drugs approved by the US Food and Drug Administration (FDA) in 2021.

Methods: DDI data for small molecular drugs approved by the FDA in 2021 (N = 36) were analyzed using the University of Washington Drug Interaction Database. The mechanism(s) and clinical magnitude of these interactions were characterized based on information available in the new drug application reviews. Clinical studies and simulation results with mean AUC ratios (AUCRs) ≥5 for inhibition DDIs and ≤0.2 for induction (ie, strong interactions) were then fully analyzed. A total of 7 drugs had an AUC change ≥5-fold as victim drugs, with inhibition and induction of cytochrome P450 (CYP) 3A explaining all interactions.

Findings: Six drugs, namely atogepant, finerenone, ibrexafungerp, infigratinib, mobocertinib, and voclosporin, were sensitive substrates of CYP3A, with AUCRs of 5.45 to 18.55 when co-administered with the strong inhibitors itraconazole or ketoconazole, whereas avacopan was a moderate sensitive substrate of CYP3A, most sensitive to induction (>5-fold change). Only 1 drug, viloxazine, was a strong perpetrator (CYP1A2 inhibition with caffeine AUCR of 5.83). No drug had strong inhibition of transporters and no strong induction of enzymes or transporters was detected. No dominant therapeutic class was identified. As expected, all these strong DDIs triggered strict labeling recommendations.

Implications: Overall, identifying strong DDIs with newly approved drugs and understanding their mechanisms are critical to provide effective management strategies in patients who often receive multiple comedications.