Drug-Drug Interactions and Kidney Disease in Hospitalized Patients

As the population ages and polypharmacy becomes increasingly common, drug-drug interactions (DDIs) grow as potential sources of morbidity and mortality. Although the literature is replete with case reports of potential DDIs, few studies have objectively quantified their clinical impact. Moreover, no previous studies have examined health outcomes related to DDI that occur in the hospital setting. Many unique factors are present in the hospitalized population that substantially limits inferences that can be made through generalizations from other settings. In particular, kidney disease is common in hospitalized patients and may exhibit bidirectional relationships with various DDIs, functioning as both an outcome of DDIs and a factor that alters the occurrence and clinical impact of DDIs. The broad objectives of this proposal are to elucidate and quantify the bidirectional relationships between renal function and DDI in the hospital setting. We will conduct a retrospective cohort study to examine whether there is a causal interaction between NSAIDs and RAS-inhibitors that increases AKI risk. We will then conduct a retrospective, multicenter cohort study of patients on inpatient warfarin therapy that will determine the effect of renal dysfunction on the magnitude of a known interaction between warfarin and amiodarone that is mediated by CYP2C9 inhibition. We have chosen warfarin as a model substrate to examine the effect of renal dysfunction on DDI magnitude because it is commonly used in hospitalized patients, its dose response is routinely monitored with the international normalized ratio (INR), and renal dysfunction is known to alter warfarin metabolism.