(1247) Pharmacodynamic Drug Interactions Associated with Acute Kidney Injury: A Literature Review and Disproportionality Analysis of Safety Signals from Spontaneous Adverse Event Reports

Objectives: To identify signals through spontaneous reports within the Food and Drug Administration’s Adverse Event Reporting System (FAERS) that support or refute drug combinations with suggested evidence of a pharmacodynamic interaction resulting in acute kidney injury (AKI).

Methods: We completed two literature reviews for articles published prior to and in the year 2022 in the PubMed and EMBASE databases to identify drug combinations that mentioned an additive or synergistic association with AKI and provided plausible mechanism(s) for the interaction. Negative controls were identified for comparison, which included drug combinations in the same classes or indications as the interacting pair with no or low association of AKI. This was followed by a disproportionality analysis using deduplicated FAERS reports from January 2004 through September 2021. We calculated reporting odds ratios (ROR) and Observed-to-Expected ratios (OER) with shrinkage, including 95% confidence intervals (CI) for both, to analyze the frequency of adverse drug events (ADE) mentioning AKI or AKI-related terms compared to the expected frequency of ADE reports that did not involve our identified drug combinations. The OER is represented as a binary logarithm, and an OER of ≥ 2.00 suggests that ≥4 times the amount of expected cases were reported for a specific combination. We plan to conduct an additional disproportionality analysis using the same strategy for several drug combinations that include known Cytochrome P450 3A4 (CYP3A4) enzyme inhibitors and substrates.

Results: Four drug combinations were identified from the literature reviews: dapagliflozin-exenatide, diclofenac-enalapril, simvastatin-gemfibrozil, and lesinurad-febuxostat. A total of 419 reports were obtained from FAERS. Most reports were for male (72.2%) with a mean age of 62 years old. All of the identified drug combinations were calculated to have RORs and OERs ≥ 2.00. The drug combination with the strongest signal and highest number of reports involving AKI-related ADEs was simvastatin-gemfibrozil (ROR 8.37, 95% CI 7.58-9.25; OER 3.05, 95% CI 2.86-3.18), while the combination with the weakest signal was dapagliflozin-exenatide (ROR 4.52, 95% CI 2.80-4.92; OER 2.02, 95% CI 1.15-2.62). All drug combinations except lesinurad-febuxostat had a higher ROR and OER than their negative control pair. Death was reported as the most severe patient outcome for 15.8% of all cases which reported an outcomes measure. Results for the specific CYP3A4-interacting drug combinations are pending.

Conclusions: N/A