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Target Adverse Event Profiles for Predictive Safety in the Postmarket Setting.

ABSTRACT: We improved a previous pharmacological target adverse-event (TAE) profile model to predict adverse events (AEs) on US Food and Drug Administration (FDA) drug labels at the time of approval. The new model uses more drugs and features for learning as well as a new algorithm. Comparator drugs sharing similar target activities to a drug of interest were evaluated by aggregating AEs from the FDA Adverse Event Reporting System (FAERS), FDA drug labels, and medical literature. An ensemble machine learning model was used to evaluate FAERS case count, disproportionality scores, percent of comparator drug labels with a specific AE, and percent of comparator drugs with the reports of the event in the literature. Overall classifier performance was F1 of 0.71, area under the precision-recall curve of 0.78, and area under the receiver operating characteristic curve of 0.87. TAE analysis continues to show promise as a method to predict adverse events at the time of approval.

SUBMITTER: Schotland P

PROVIDER: S-EPMC8246740 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Target Adverse Event Profiles for Predictive Safety in the Postmarket Setting.

Schotland Peter P Racz Rebecca R Jackson David B DB Soldatos Theodoros G TG Levin Robert R Strauss David G DG Burkhart Keith K

Clinical pharmacology and therapeutics 20201107 5

We improved a previous pharmacological target adverse-event (TAE) profile model to predict adverse events (AEs) on US Food and Drug Administration (FDA) drug labels at the time of approval. The new model uses more drugs and features for learning as well as a new algorithm. Comparator drugs sharing similar target activities to a drug of interest were evaluated by aggregating AEs from the FDA Adverse Event Reporting System (FAERS), FDA drug labels, and medical literature. An ensemble machine learn ...[more]

PMID: 33090463

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Project description:BackgroundAdalimumab has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult rheumatoid arthritis (RA), and subsequently approved for pediatric treatment of various autoimmune diseases in children of different ages. Due to genetic differences between children and adults in terms of physiology and immunity, there is a need to explore the safety of adalimumab in children in the real world. The aim of this study is to identify potential adverse event (AE) signals associated with the use of adalimumab in pediatric patients (<18 years old) using data from the FDA Adverse Event Reporting System (FAERS).MethodsAEs associated with adalimumab in pediatric patients reported in the FAERS database from the first quarter (Q1) of 2017 to the third quarter (Q3) of 2022 were systematically gathered. Reporting odds ratio (ROR), the proportional reporting ratio (PRR), the information component (IC), and the empirical Bayes geometric mean (EBGM) were used to assess the relationship between adalimumab and AEs in children.ResultsOut of 8,363,304 reports collected from the FAERS database during the study period, 3819 reports on children on adalimumab were identified. Adalimumab-related AEs reports were concentrated on 10 toxicity areas and a total of 202 positive signals were detected, of which injection site papule (ROR = 261.97) and intestinal fistula (ROR = 122.09) had the strongest signals. Unexpected significant AEs, including intestinal obstruction, immunodeficiency, abdominal abscess, and Takayasu's arteritis might also occur. In comparison with patients of all ages in the same time window, the median onset time of children was shorter (99 vs. 149 days). Most of the AE cases occurred in children within the first 1 (1.71%), 2 (8.12%), and 3 months (8.39%) and had early failure types after adalimumab initiation. Methotrexate, folic acid, prednisone, azathioprine, and mesalamine were the top five drugs used concomitantly for adalimumab-associated AEs.ConclusionsWhen adalimumab is used in children, especially in the first 3 months of treatment, in addition to the AEs recorded in the drug package insert, close attention should be paid to the new potential AEs off-label to ensure the safety of adalimumab in children.

Project description:ObjectivesPaclitaxel is a highly effective antitumor agent with notable adverse events, including hypersensitivity reactions, peripheral neuropathy, arthralgia, myalgias, and neutropenia. Solvent-based paclitaxel causes severe allergic, hypersensitivity, and anaphylactic reactions. Nanoparticle albumin-bound paclitaxel was recently developed and provides an advantage over solvent-based paclitaxel in avoiding solvent/surfactant-related adverse events. The aim of this study was to assess the adverse event profiles of solvent-based paclitaxel and nanoparticle albumin-bound paclitaxel formulations using data from the spontaneous adverse event reporting system of the US Food and Drug Administration Adverse Event Reporting System database.MethodsThis study relied on Medical Dictionary for Regulatory Activities preferred terms and standardized queries, and calculated the reporting ratio and reporting odds ratios of paclitaxel formulations.ResultsOf 8,867,135 reports recorded in the US Food and Drug Administration Adverse Event Reporting System database from January 2004 to December 2016, 3469 and 4447 adverse events corresponded to solvent-based paclitaxel and nanoparticle albumin-bound paclitaxel, respectively. Reporting odds ratios (95% confidence interval) for anaphylactic reaction (standardized MedDRA query code: 20000021) associated with the use of solvent-based paclitaxel and nanoparticle albumin-bound paclitaxel were 1.69 (1.56-1.84) and 0.75 (0.68-0.83), respectively. Reporting odds ratio signal for anaphylactic reaction was not detected for nanoparticle albumin-bound paclitaxel. Reporting odds ratios (95% confidence interval) for acute renal failure (standardized MedDRA query code: 20000003) associated with the use of solvent-based paclitaxel and nanoparticle albumin-bound paclitaxel were 0.75 (0.58-0.98) and 1.60 (1.37-1.89), respectively.ConclusionThis is the first study to evaluate the adverse event profile of nanoparticle albumin-bound paclitaxel using US Food and Drug Administration Adverse Event Reporting System data. Considering that the US Food and Drug Administration Adverse Event Reporting System database does not allow to infer causality or risk ranking, the different reporting frequencies of anaphylactic reaction and acute renal failure between solvent-based paclitaxel and nanoparticle albumin-bound paclitaxel must be further investigated via analytical observational research.

Dataset Information

Target Adverse Event Profiles for Predictive Safety in the Postmarket Setting.

Publications

Target Adverse Event Profiles for Predictive Safety in the Postmarket Setting.

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