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  1. With increasing trend of polypharmacy, drug‐drug interaction (DDI)‐induced adverse drug events (ADEs) are considered as a major challenge for clinical practice. As premarketing clinical trials usually have stringent inclusion/exclusion criteria, limited comedication data capture and often times small sample size have limited values in study DDIs. On the other hand, ADE reports collected by spontaneous reporting system (SRS) become an important source for DDI studies. There are two major challenges in detecting DDI signals from SRS: confounding bias and false positive rate. In this article, we propose a novel approach, propensity score‐adjusted three‐component mixture model (PS‐3CMM). This model can simultaneously adjust for confounding bias and estimate false discovery rate for all drug‐drug‐ADE combinations in FDA Adverse Event Reporting System (FAERS), which is a preeminent SRS database. In simulation studies, PS‐3CMM performs better in detecting true DDIs comparing to the existing approach. It is more sensitive in selecting the DDI signals that have nonpositive individual drug relative ADE risk (NPIRR). The application of PS‐3CMM is illustrated in analyzing the FAERS database. Compared to the existing approaches, PS‐3CMM prioritizes DDI signals differently. PS‐3CMM gives high priorities to DDI signals that have NPIRR. Both simulation studies and FAERS data analysis conclude that our new PS‐3CMM is a new method that is complement to the existing DDI signal detection methods.

     
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  2. Pharmacoinformatics research has experienced a great deal of successes in detecting drug‐induced adverse events (AEs) using large‐scale health record databases. In the era of polypharmacy, pharmacoinformatics faces many new challenges, and two significant challenges are to detect high‐order drug interactions and to handle strongly correlated drugs. In this article, we propose a super‐combo‐drug test (SupCD‐T) to address the aforementioned two challenges. SupCD‐T detects drug interactions by identifying optimal drug combinations with increased AE risks. In addition, SupCD‐T increases the statistical powers to detect single‐drug effects by combining strongly correlated drugs. Although SupCD‐T does not distinguish single‐drug effects from their combination effects, it is noticeably more powerful in selecting an individual drug effect in the multiple regression analysis, where confounding justification between two correlated drugs reduces the power in testing the individual drug effects on AEs. Our simulation studies demonstrate that SupCD‐T has generally better power comparing with the multiple regression analysis. In addition, SupCD‐T is able to select meaningful drug combinations (eg, highly coprescribed drugs). Using electronic health record database, we illustrate the utility of SupCD‐T and discover a number of drug combinations that have increased risk in myopathy. Some novel drug combinations have not yet been investigated and reported in the pharmacology research.

     
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  3. Background

    While the pharmacokinetic (PK) mechanisms for many drug interactions (DDIs) have been established, pharmacovigilance studies related to these PK DDIs are limited. Using a large surveillance database, a translational informatics approach can systematically screen adverse drug events (ADEs) for many DDIs with known PK mechanisms.

    Methods

    We collected a set of substrates and inhibitors related to the cytochrome P450 (CYP) isoforms, as recommended by the United States Food and Drug Administration (FDA) and Drug Interactions Flockhart table™. The FDA's Adverse Events Reporting System (FAERS) was used to obtain ADE reports from 2004 to 2018. The substrate and inhibitor information were used to form PK DDI pairs for each of the CYP isoforms and Medical Dictionary for Regulatory Activities (MedDRA) preferred terms used for ADEs in FAERS. A shrinkage observed‐to‐expected ratio (Ω) analysis was performed to screen for potential PK DDI and ADE associations.

    Results

    We identified 149 CYP substrates and 62 CYP inhibitors from the FDA and Flockhart tables. Using FAERS data, only those DDI‐ADE associations were considered that met the disproportionality threshold ofΩ > 0 for a CYP substrate when paired with at least two inhibitors. In total, 590 ADEs were associated with 2085 PK DDI pairs and 38 individual substrates, with ADEs overlapping across different CYP substrates. More importantly, we were able to find clinical and experimental evidence for the paclitaxel‐clopidogrel interaction associated with peripheral neuropathy in our study.

    Conclusion

    In this study, we utilized a translational informatics approach to discover potentially novel CYP‐related substrate‐inhibitor and ADE associations using FAERS. Future clinical, population‐based and experimental studies are needed to confirm our findings.

     
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  4. Drug‐drug interactions (DDIs) are a common cause of adverse drug events (ADEs). The electronic medical record (EMR) database and the FDA's adverse event reporting system (FAERS) database are the major data sources for mining and testing the ADE associated DDI signals. Most DDI data mining methods focus on pair‐wise drug interactions, and methods to detect high‐dimensional DDIs in medical databases are lacking. In this paper, we propose 2 novel mixture drug‐count response models for detecting high‐dimensional drug combinations that induce myopathy. The “count” indicates the number of drugs in a combination. One model is called fixed probability mixture drug‐count response model with a maximum risk threshold (FMDRM‐MRT). The other model is called count‐dependent probability mixture drug‐count response model with a maximum risk threshold (CMDRM‐MRT), in which the mixture probability is count dependent. Compared with the previous mixture drug‐count response model (MDRM) developed by our group, these 2 new models show a better likelihood in detecting high‐dimensional drug combinatory effects on myopathy. CMDRM‐MRT identified and validated (54; 374; 637; 442; 131) 2‐way to 6‐way drug interactions, respectively, which induce myopathy in both EMR and FAERS databases. We further demonstrate FAERS data capture much higher maximum myopathy risk than EMR data do. The consistency of 2 mixture models' parameters and local false discovery rate estimates are evaluated through statistical simulation studies.

     
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