Use of a Bioinformatics-Based Toxicity Scoring System to Assess Serotonin Burden and Predict Population-Level Adverse Drug Events from Concomitant Serotonergic Drug Therapy.

STUDY OBJECTIVE: Numerous medications interact at serotonin (5-hydroxytryptamine [5-HT]) receptors directly or through off-target interactions, causing mild to severe serotonergic adverse drug events (ADEs), particularly among older adults. Our objective was to develop a novel molecular-based toxicity scoring system to assess serotonergic burden resulting from concurrently administered drugs. Quantitative methods to assess serotonergic burden may provide a useful clinical tool for improving pharmacotherapy. DESIGN: Retrospective cohort study. DATA SOURCES: PharMetrics Legacy health claims database (January 2001-December 2013) and ChEMBL bioactivity database. PATIENTS: A 2-serotonergic drug exposure cohort (78,172 patients) and a 3-serotonergic drug exposure cohort (19,900 patients) were generated, and population-level statistics were collected. Nonexposure cohorts were created for each drug exposure cohort and matched in a 4:1 ratio for age, sex, and length of enrollment. MEASUREMENTS AND MAIN RESULTS: Eight 5-HT medications were screened against multiple bioactivity databases to identify their off-target interactions at 5-HT receptors and serotonin reuptake transporter protein. A computational serotonin burden score (SBS) was derived from the receptor-specific interaction propensities reported from the comprehensive bioactivity screen. Linear regression was used to characterize associations between SBSs and combined total ADE incidence rate detected by International Classification of Diseases, Ninth Revision, Clinical Modification, diagnosis codes. A significantly greater incidence of 17 potential 5-HT-related ADEs was seen in exposed serotonergic drug cohorts (p<0.05). A positive correlation between SBS and overall ADE incidence rate in the 2-serotonergic drug exposure cohort (R2  = 0.69, p<0.34) and 3-drug cohort (R2  = 0.85, p<0.01) was observed. When both drug cohorts were combined, total drug SBSs strongly correlated with the composite 5-HT adverse event rate (R2  = 0.92, p<0.0001). Despite an increasing burden of illness, these data suggest that drug combinations with higher SBSs are associated with a higher rate of potential serotonergic ADEs. CONCLUSION: In this test of concept, positive associations between SBSs and serotonin-related ADEs suggest that it may offer a pharmacologic-based foundation for developing risk assessment tools to assist in optimizing pharmacotherapy.

Implications of Off-Target Serotoninergic Drug Activity: An Analysis of Serotonin Syndrome Reports Using a Systematic Bioinformatics Approach.

STUDY OBJECTIVE: Serotonergic adverse drug events (ADEs) are caused by enhanced intrasynaptic concentrations of 5-hydroxytryptamine (5-HT). No systematic process currently exists for evaluating cumulative 5-HT and off-target toxicity of serotonergic drugs. The primary study aim was to create a Serotonergic Expanded Bioactivity Matrix (SEBM) by using a molecular bioinformatics, polypharmacologic approach for assessment of the participation of individual 5-HT drugs in serotonin syndrome (SS) reports. DATA SOURCES: Publicly available databases including the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), ChEMBL, DrugBank, PubChem, and Kyoto Encyclopedia of Genes and Genomes (KEGG) were queried for computational and pharmacologic data. DESIGN: An in-house bioinformatics TargetSearch program ( http://dxulab.org/software) was used to characterize 71 serotonergic drugs interacting at 13 serotonin receptor subtypes and serotonin reuptake transporter protein (SERT). In addition, off-target interactions at norepinephrine transporter (NET), monoamine oxidase (MAO), and muscarinic receptors were included to define seven polypharmacological drug cohorts. Serotonin syndrome reports for each serotonergic drug were extracted from FAERS by using the Sternbach and Hunter criteria. MEASUREMENTS AND MAIN RESULTS: A proportional reporting adverse drug reaction (ADR) ratio (PRR) was calculated from each drug's total ADEs and SS case reports and aggregated by drug bioactivity cohorts. Triple-receptor interactions had a disproportionately higher number of SS cases using both the Hunter criteria (mean PRR 1.72, 95% CI 1.05-2.39) and Sternbach (mean PRR 1.54, 95% CI 1.29-1.79). 5-Hydroxytryptamine agonists were associated with a significantly lower proportion of SS cases using the Hunter and Sternbach criteria, respectively (mean PRR 0.49, 95% CI 0.17-0.81 and mean PRR 0.49, 95% CI 0.15-0.83). Drugs with disproportionately higher participation in SS vary considerably between the two diagnostic criteria. CONCLUSION: The SEBM model suggests a possible polypharmacological role in SS. Although further research is needed, off-target receptor activity may help explain differences in severity of toxicity and clinical presentation.

MSBIS: A Multi-Step Biomedical Informatics Screening Approach for Identifying Medications that Mitigate the Risks of Metoclopramide-Induced Tardive Dyskinesia.

In 2009 the U.S. Food and Drug Administration (FDA) placed a black box warning on metoclopramide (MCP) due to the increased risks and prevalence of tardive dyskinesia (TD). In this study, we developed a multi-step biomedical informatics screening (MSBIS) approach leveraging publicly available bioactivity and drug safety data to identify concomitant drugs that mitigate the risks of MCP-induced TD. MSBIS includes (1) TargetSearch (http://dxulab.org/software) bioinformatics scoring for drug anticholinergic activity using CHEMBL bioactivity data; (2) unadjusted odds ratio (UOR) scoring for indications of TD-mitigating effects using the FDA Adverse Event Reporting System (FAERS); (3) adjusted odds ratio (AOR) re-scoring by removing the effect of cofounding factors (age, gender, reporting year); (4) logistic regression (LR) coefficient scoring for confirming the best TD-mitigating drug candidates. Drugs with increasing TD protective potential and statistical significance were obtained at each screening step. Fentanyl is identified as the most promising drug against MCP-induced TD (coefficient: -2.68; p-value<0.01). The discovery is supported by clinical reports that patients fully recovered from MCP-induced TD after fentanyl-induced general anesthesia. Loperamide is identified as a potent mitigating drug against a broader range of drug-induced movement disorders through pharmacokinetic modifications. Using drug-induced TD as an example, we demonstrated that MSBIS is an efficient in silico tool for unknown drug-drug interaction detection, drug repurposing, and combination therapy design.

Assessing and predicting drug-induced anticholinergic risks: an integrated computational approach.

BACKGROUND: Anticholinergic (AC) adverse drug events (ADEs) are caused by inhibition of muscarinic receptors as a result of designated or off-target drug-receptor interactions. In practice, AC toxicity is assessed primarily based on clinician experience. The goal of this study was to evaluate a novel concept of integrating big pharmacological and healthcare data to assess clinical AC toxicity risks. METHODS: AC toxicity scores (ATSs) were computed using drug-receptor inhibitions identified through pharmacological data screening. A longitudinal retrospective cohort study using medical claims data was performed to quantify AC clinical risks. ATS was compared with two previously reported toxicity measures. A quantitative structure-activity relationship (QSAR) model was established for rapid assessment and prediction of AC clinical risks. RESULTS: A total of 25 common medications, and 575,228 exposed and unexposed patients were analyzed. Our data indicated that ATS is more consistent with the trend of AC outcomes than other toxicity methods. Incorporating drug pharmacokinetic parameters to ATS yielded a QSAR model with excellent correlation to AC incident rate (R2 = 0.83) and predictive performance (cross validation Q2 = 0.64). Good correlation and predictive performance (R2 = 0.68/Q2 = 0.29) were also obtained for an M2 receptor-specific QSAR model and tachycardia, an M2 receptor-specific ADE. CONCLUSIONS: Albeit using a small medication sample size, our pilot data demonstrated the potential and feasibility of a new computational AC toxicity scoring approach driven by underlying pharmacology and big data analytics. Follow-up work is under way to further develop the ATS scoring approach and clinical toxicity predictive model using a large number of medications and clinical parameters.

Perceptions of practicing pharmacists in Idaho about a potential behind-the-counter drug program.

BACKGROUND: In late 2007, the Food and Drug Administration (FDA) held public hearings exploring the establishment of a new behind-the-counter (BTC) drug program. However, little is known about the views of pharmacists regarding such a program. OBJECTIVE: To assess the overall perceptions of Idaho's practicing pharmacists about the creation of a formal BTC drug program, the appropriateness of including certain drug categories, specific barriers to its adoption, and the impact of the new program on access to medicines. METHODS: A survey of practicing pharmacists in Idaho was conducted by mail, utilizing anonymous responses. Key questions exploring the views of pharmacists about the new BTC drug program utilized 5-point Likert scales. Data were also collected on respondent characteristics. RESULTS: A total of 357 practicing pharmacists in Idaho (31% response rate) returned the mail survey; 84% of pharmacists agreed that the FDA should be exploring an expanded BTC program, and 88% of pharmacists agreed that this program would improve access to some prescription-only products and convenience for patients. Almost 71% of pharmacists reported a personal willingness to both initiate and monitor certain BTC drug therapies. When focusing on specific drug categories for BTC status, the highest support was for selected agents within smoking cessation therapies (85%), nasal corticosteroids for allergies (81%), and vaccines (75%). Pharmacists who reported low barriers to the adoption of a new BTC program were significantly more likely to support this program than were those reporting high barriers. Only 39% of pharmacists agreed that adequate facilities were currently available for private evaluation and counseling of BTC patients. CONCLUSIONS: Pharmacists in a statewide survey of perceptions regarding a new BTC drug program overwhelmingly believe that patients would benefit. Pharmacists strongly support the development of the new program, and more than two thirds indicate that they would likely participate, given the necessary supporting institutional framework. Perceived barriers are related to willingness to participate and likely can be minimized through education and provision of private consulting areas.

Comparing medical cost of care for patients with metastatic breast cancer receiving taxane therapy: claims analysis.

BACKGROUND: It has been estimated that more than $8 billion is spent annually on the management of breast cancer in the United States. The taxane chemotherapeutic agents are cornerstones in the treatment of breast cancer, yet no study has assessed whether the choice of a taxane affects the economic outcomes of metastatic breast cancer treatment. OBJECTIVE: To determine if differences exist in the medical cost of care in patients receiving taxane-based chemotherapy for metastatic breast cancer, and to compare the use of ancillary medications (for neutropenia, anemia, and nausea and vomiting) and their associated costs among taxanes. METHOD: We identified women with metastatic breast cancer based on diagnosis codes and the women's previous adjuvant chemotherapeutic regimens. Paid medical insurance claims were captured for the 24-month study period, from January 1, 2006, through December 31, 2007. The groups were determined according to the specific taxane administered. Total medical costs were captured from the date of first taxane administration to the end of data availability. Outpatient pharmacy costs were not available. A multivariate analysis was used to evaluate the total medical costs in each group. Median total medical costs per patient per month during the study period were adjusted using a multiple regression analysis. Utilization and cost of medications administered in the office or hospital for chemotherapy-induced adverse effects were captured and adjusted with Tobit models. RESULTS: Of the 2245 study participants, 1035 received docetaxel, 997 received generic paclitaxel, and 213 received nab-paclitaxel. On average, patients in the nab-paclitaxel group received more doses (9.6) than those in the generic paclitaxel (6.0) or docetaxel (4.8) groups. The multivariate analysis was robust, explaining 72% of the variability in total medical costs across the 3 taxane groups. Median per-patient per-month total medical costs for study participants were within approximately $800 of each other among the groups. Generic paclitaxel had the lowest total medical costs. The total costs for docetaxel and nab-paclitaxel were not significantly different. Nab-paclitaxel had the lowest utilization and lowest costs associated with colony-stimulating factors. The proportion of patients receiving erythropoiesis-stimulating agents was not significantly different among the 3 drugs, but the costs for these agents were significantly lower in patients receiving nab-paclitaxel than in those receiving docetaxel. Antiemetic use was highest in the docetaxel group, but the costs for antiemetics were not different among the 3 taxane groups. CONCLUSION: The differences in total medical costs among the 3 taxanes were modest. Total medical costs were lowest for patients receiving generic paclitaxel and comparable between the docetaxel and nab-paclitaxel groups. Patients taking nab-paclitaxel received more doses than patients taking the other taxanes. Nab-paclitaxel was associated with lower utilization and costs for colony-stimulating factors compared with generic paclitaxel and docetaxel.

Pharmaceutical care plan examinations to identify students at risk for poor performance in advanced pharmacy practice experiences.

OBJECTIVES: To evaluate early predictors of advanced pharmacy practice experience (APPE) performance using either timed pharmaceutical care plan (TPCP) reports of 4 case histories or traditional lecture-based pharmacotherapy course examinations. METHODS: Statistical process control (SPC) methods were used to identify a group of third-year pharmacy students "at risk" for poor APPE performance (defined as an APPE grade point average of < 3.0). Examination scores from an integrated lecture-based pharmacotherapy sequence were used for comparison. RESULTS: TPCP scores but not lecture-based examination scores successfully identified 6 of 10 students who ultimately performed poorly in their APPEs. CONCLUSION: Adaptation of SPC methods to assess student performance during problem-based learning (PBL) case reports is a useful technique for identifying students "at risk" for poor APPE performance.

Retrospective detection of potential medication errors involving drugs with similar names.

OBJECTIVE: To estimate frequencies of potential errors involving similarly named drugs using a retrospective claims database and measure the association between frequencies of potential errors and two measures of drug name similarity, edit distance (minimum number of insertions, substitutions, or deletions of characters required to change a given word into another target word) and normalized edit distance (proportion of letters that must be changed to commute one word to another, and ranges from 0 to 1, with 0 indicating identical words, and 1 indicating a pair of words with no common letters). DESIGN: Retrospective database analysis. SETTING: Idaho Medicaid claims data from 1993 to 2000. PATIENTS: Not applicable. INTERVENTION: Potential errors were detected using adjacent claims generated by dispensing of one drug followed by dispensing of the other drug with a similar name. In all, four potential error criteria were developed: two for detecting potential refill errors and two for detecting potential initial errors. A total of 10 drug pairs were randomly selected from the Idaho Medicaid claims database for each value of edit distance, which ranged from 1 to 30 (n = 300). MAIN OUTCOME MEASURES: Frequencies of potential medication errors in claims sequences for initial and refill claims, edit distance, and normalized edit distance. RESULTS: Of 300 drug pairs studied, 106 (35.33%) were involved in at least one potential error. A total of 1,138 dispensing episodes satisfied the criteria for potential errors. Frequencies of potential errors per drug pair were negatively associated with edit distance (r = -0.133, P < .05) and normalized edit distance (r = -0.226, P < .01). Frequencies of potential initial errors also were negatively associated with edit distance (r = -0.126, P < .05) and normalized edit distance (r = -0.222, P < .01). Potential refill errors also had negative association with edit distance (r = -0.134, P < .05) and normalized edit distance (r = -0.226, P < .01). CONCLUSION: Error criteria were successfully applied to a retrospective claims database to detect potential initial and refill errors that involved similarly named drugs.

Ambulatory care increased vitamin B12 requirement associated with chronic acid suppression therapy.

BACKGROUND: Assimilation of vitamin B(12) from dietary sources requires gastric acid. By decreasing acid production, the proton pump inhibitors (PPIs) and histamine(2) (H(2))-blockers may reduce vitamin B(12) absorption. OBJECTIVE: To determine whether chronic acid suppression therapy is associated with the initiation of vitamin B(12) supplementation, we conducted a retrospective case-control study using a state-wide Medicaid population. METHODS: Case patients were identified as those who initiated vitamin B(12) supplementation during the study period. Four control patients were age- and gender-matched to each case. Patients (n = 109 844) with a paid claim between September 27, 1995, and September 27, 1997, were eligible for inclusion. Chronic acid suppression therapy was defined as treatment with H(2)-blockers or PPIs for >/=10 of the 12 months prior to the first vitamin B(12) injection. Comparisons were made between the case and control groups regarding exposure to chronic acid suppression therapy. RESULTS: One hundred twenty-five cases were matched to 500 controls. Twenty-three patients (18.4%) had been exposed to chronic acid suppression therapy compared with 55 (11.0%) of the control group (p = 0.025; OR 1.82; 95% CI 1.08 to 3.09). CONCLUSIONS: Initiation of vitamin B(12) supplementation was associated with chronic gastric acid suppression therapy.