Real-World Medication Utilization and Potential Pharmacokinetic Drug–Drug Interaction Liabilities in Patients with Heart Failure and Chronic Kidney Disease

Background/Objectives: Patients with heart failure (HF) and chronic kidney disease (CKD) frequently receive complex multidrug regimens, increasing the potential for pharmacokinetic drug–drug interactions (DDIs). Methods: This study used U.S. Optum® claims data from the period 2019–2024 to characterize medication use prevalence in adults with HF or CKD and identify potential DDI liabilities by mapping commonly used medications to established cytochrome P450 (CYP) enzyme and transporter pathways. Potential mechanistic interactions with guideline-directed medical therapy were further prioritized using a semi-quantitative framework based on perpetrator strength and substrate sensitivity, with Tier 1 and Tier 2 representing higher-priority CYP-mediated interaction candidates. Results: The analysis included 856,041 patients with HF and 1,893,827 patients with CKD, with median ages of 75 and 72 years, respectively. In CKD, atorvastatin (25.7%) and metformin (19.1%) were among the most prevalent medications, while metoprolol (33.2%) and furosemide (31.9%) were highly prevalent in HF. Many commonly used medications had established substrate or inhibitor liabilities involving CYP3A, CYP2D6, and transporters including P-gp, OATP1B, MATE, OCT2, and BCRP. CYP3A liabilities were identified in 13 of the 25 most frequently used medications in each population. Higher-priority potential interactions were pathway-specific, with Tier 1 and Tier 2 candidates primarily involving CYP3A in CKD and CYP2D6 in HF. Integrating real-world medication prevalence with established mechanistic DDI information provides a practical, hypothesis-generating framework for identifying and prioritizing potential pharmacokinetic DDI liabilities in HF and CKD. Conclusions: These findings may inform subsequent DDI evaluations and clinical pharmacology study planning to support drug development and future risk-mitigation strategies, although actual co-exposure, clinical DDIs, and associated outcomes were not assessed.