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Drug Safety Jun 2024There is a need to strengthen the evidence base regarding medication use during pregnancy and to facilitate the early detection of safety signals. EudraVigilance (EV)...
INTRODUCTION
There is a need to strengthen the evidence base regarding medication use during pregnancy and to facilitate the early detection of safety signals. EudraVigilance (EV) serves as the primary system for managing and analysing information concerning suspected adverse drug reactions (ADRs) within the European Economic Area. Despite its various functionalities, the current format for electronic submissions of safety reports lacks a specific data element indicating medicine exposure during pregnancy.
OBJECTIVE
This paper aims to address the limitations of existing approaches by developing a rule-based algorithm in EV that more reliably identifies cases that are truly representative of an ADR during pregnancy.
METHODS
The study utilised the standardised MedDRA query (SMQ) 'Pregnancy and neonatal topics' (PNT) as a benchmark for comparison. Recognising that the SMQ PNT also retrieves healthy pregnancy outcomes, contraceptive failure, failed abortifacients as well as ADRs not associated with pregnancy, a novel algorithm was tailored to improve the accuracy of identifying suspected ADRs occurring during pregnancy.
RESULTS
Upon testing, the algorithm demonstrated superior performance, correctly predicting 90% of cases reporting an ADR during pregnancy, compared to 54% achieved by the SMQ PNT. The implementation of the algorithm in EV led to the retrieval of 202,426 cases.
CONCLUSION
The development and successful testing of the novel algorithm represents a step forward in pregnancy-specific signal detection in EV. Because signals associated with pregnancy may be diluted in a large database such as EV, this study lays the groundwork for future research to evaluate the effectiveness of disproportionality methods on a more refined subset of pregnancy-related ADR reports.
PubMed: 38896215
DOI: 10.1007/s40264-024-01448-y -
Clinical Chemistry and Laboratory... Jun 2024Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of severe fluoropyrimidine-related toxicities. The best strategy for identifying DPD-deficient...
OBJECTIVES
Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of severe fluoropyrimidine-related toxicities. The best strategy for identifying DPD-deficient patients is still not defined. The EMA recommends targeted genotyping or uracilemia (U) testing. We analyzed the concordance between both approaches.
METHODS
This study included 19,376 consecutive French patients with pre-treatment plasma U, UH2 and targeted genotyping (*2A, *13, D949V, *7) analyzed at Eurofins Biomnis (2015-2022).
RESULTS
Mean U was 9.9 ± 10.1 ng/mL (median 8.7, range 1.6-856). According to French recommendations, 7.3 % of patients were partially deficient (U 16-150 ng/mL) and 0.02 % completely deficient (U≥150 ng/mL). variant frequencies were *2A: 0.83 %, *13: 0.17 %, D949V: 1.16 %, *7: 0.05 % (2 homozygous patients with U at 22 and 856 ng/mL). Variant carriers exhibited higher U (median 13.8 vs. 8.6 ng/mL), and lower UH2/U (median 7.2 vs. 11.8) and UH2/U (median 0.54 vs. 1.37) relative to wild-type patients (p<0.00001). Sixty-six% of variant carriers exhibited uracilemia <16 ng/mL, challenging correct identification of DPD deficiency based on U. The sensitivity (% patients with a deficient phenotype among variant carriers) of U threshold at 16 ng/mL was 34 %. The best discriminant marker for identifying variant carriers was UH2/U. UH2/U<0.942 (29.7 % of patients) showed enhanced sensitivity (81 %) in identifying deleterious genotypes across different variants compared to 16 ng/mL U.
CONCLUSIONS
These results reaffirm the poor concordance between DPD phenotyping and genotyping, suggesting that both approaches may be complementary and that targeted genotyping is not sufficiently reliable to identify all patients with complete deficiency.
PubMed: 38896022
DOI: 10.1515/cclm-2024-0317 -
Journal of Clinical Medicine Jun 2024: In the context of a comparative study of efficacy and safety of drugs used in rare neuromuscular and neurodegenerative diseases (CAESAR-call AIFA_FV_2012-13-14), we...
: In the context of a comparative study of efficacy and safety of drugs used in rare neuromuscular and neurodegenerative diseases (CAESAR-call AIFA_FV_2012-13-14), we assessed the use patterns of drugs indicated for myasthenia gravis (MG). : A retrospective cohort study was conducted based on administrative healthcare data. For a cohort of MG patients, prevalent and incident use of pyridostigmine (Py) and other indicated drugs in the first year after case identification was evaluated. Prevalent combined use of major therapies (azathioprine (Az), prednisone (Pr), vitamin D (Vd)) stratified by Py use was assessed, and a comparison between therapies at the time of MG identification and during the first year of follow-up was performed. : We included 2369 MG patients between 2013 and 2019. Among them, prevalent and incident Py users were 38.4% and 22.0%, respectively. In the first year of follow-up, the use of Pr was observed in 74.5% of Py prevalent users and in 82.0% of Py incident users, respectively; the use of Az was observed in 24.9% and 23.0%, respectively; and the use of Vd was observed in 53.3% and 48.2%, respectively. Among 910 Py prevalent users, 13.1% also used Az, Pr, and Vd, while 15.3% used none of these. Among 938 non-Py users, 2.7% used Az, Pr, and Vd, while 53.8% used none of these. During the first year, an increase in combined therapies was evident in incident Py users. : Our results suggest that, for some MG patients, there may be a need for treatments that combine a rapid onset of benefit with long-term and consistent disease control. These issues may be addressed by the new treatments currently being developed. To date, more studies are needed to address the heterogeneity, quality, and generalizability of the existing data and to evaluate patterns of use, efficacy, and safety of new or emerging therapies for MG.
PubMed: 38893023
DOI: 10.3390/jcm13113312 -
Journal of Clinical Medicine May 2024Vericiguat was developed to treat patients with heart failure (HF). Currently, limited data are available to characterize vericiguat-treated patients in real-world...
Vericiguat was developed to treat patients with heart failure (HF). Currently, limited data are available to characterize vericiguat-treated patients in real-world clinical settings. This retrospective cohort study was done using a Japanese hospital administrative database to describe the use of vericiguat in patients with HF in real-world settings. Adult patients diagnosed with HF prescribed vericiguat between 1 July 2021 and 30 September 2022 were included. Patient characteristics at the initiation of vericiguat treatment, patterns of HF medication use, and vericiguat dose titrations were assessed within the first 90 days of treatment. The study included 829 patients who were initiated on vericiguat therapy. The mean age was 75.5 years and 69.0% were male. Hypertension, coronary artery disease, and diabetes mellitus were present in 91.7, 71.3, and 60.1% of patients, respectively. Most patients had previously received HF medications, with high percentages using angiotensin-receptor blocker neprilysin inhibitors (ARNI; 43.9%) and sodium-glucose cotransporter-2 inhibitors (54.4%). During the first 90 days of vericiguat treatment, 65.8% of the patients were uptitrated from their starting dose, and 32.3% had reached the maximal daily dose. The median time to reach the maximal daily dose was 34 days. The multivariable model identified that initiating vericiguat treatment in an outpatient setting and using ARNI before initiating vericiguat treatment were factors significantly associated with reaching the maximal daily dose of vericiguat at any given time, whereas older age, chronic kidney disease, hyperkalemia, and anemia were not associated. These findings provide early insights into the use of vericiguat, which aid in optimizing the combinations and/or sequences of HF treatment incorporating vericiguat therapy.
PubMed: 38892932
DOI: 10.3390/jcm13113222 -
BMC Women's Health Jun 2024The SCHUMANN study evaluated the efficacy and safety of the selective P2 × 3 antagonist eliapixant in patients with endometriosis-associated pelvic pain (EAPP). (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The SCHUMANN study evaluated the efficacy and safety of the selective P2 × 3 antagonist eliapixant in patients with endometriosis-associated pelvic pain (EAPP).
METHODS
SCHUMANN was a randomized, placebo- and active comparator-controlled, double-blind to placebo and open-label to comparator, parallel-group, multicenter, dose-finding phase 2b study. The participants were women with surgically diagnosed endometriosis who fulfilled defined EAPP criteria. Participants were randomized 1:1:1:1 to twice daily (BID) 25 mg, 75 mg, or 150 mg oral eliapixant or a placebo for 12 weeks. An exploratory once-daily elagolix 150 mg treatment group was also included. The primary endpoint was the absolute change in mean worst EAPP from baseline to the end of intervention (EOI).
RESULTS
Overall, 215 participants were randomized for treatment (44 to eliapixant 25 mg, 44 to eliapixant 75 mg, 43 to eliapixant 150 mg, 43 to a placebo, and 41 to elagolix 150 mg). For safety reasons, the study was terminated early; both treatment and enrollment stopped immediately, producing less than 50% of the planned number of completers. The study found no significant differences in EAPP reduction from baseline between groups and no significant dose-response model. The elagolix 150 mg group showed better pain reduction than any of the other groups. No new safety signals were observed, relative to the previously known safety profile of eliapixant, which was generally well tolerated. However, one case of moderate and probably drug-induced liver injury in a participant receiving eliapixant 150 mg BID supported the association between eliapixant and a potential increase in liver function values, defined before the start of the phase 2 program.
CONCLUSIONS
This study did not meet its primary objective as no statistically significant or clinically relevant differences in changes of mean worst EAPP from baseline were observed between treatment groups. The single observed case of moderate, probably drug-induced liver injury was the second case in the eliapixant phase 2 program conducted in the following indications: refractory or unexplained chronic cough, diabetic neuropathic pain, overactive bladder, and EAPP. Due to this, the benefit-risk ratio for the study was no longer considered to be positive.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov identifier NCT04614246; registered November 3, 2020.
Topics: Humans; Female; Endometriosis; Pelvic Pain; Adult; Double-Blind Method; Treatment Outcome; Middle Aged; Hydrocarbons, Fluorinated; Dose-Response Relationship, Drug; Pain Measurement; Pyrimidines
PubMed: 38890641
DOI: 10.1186/s12905-024-03188-8 -
Journal of Medical Internet Research Jun 2024To mitigate safety concerns, regulatory agencies must make informed decisions regarding drug usage and adverse drug events (ADEs). The primary pharmacovigilance data...
BACKGROUND
To mitigate safety concerns, regulatory agencies must make informed decisions regarding drug usage and adverse drug events (ADEs). The primary pharmacovigilance data stem from spontaneous reports by health care professionals. However, underreporting poses a notable challenge within the current system. Explorations into alternative sources, including electronic patient records and social media, have been undertaken. Nevertheless, social media's potential remains largely untapped in real-world scenarios.
OBJECTIVE
The challenge faced by regulatory agencies in using social media is primarily attributed to the absence of suitable tools to support decision makers. An effective tool should enable access to information via a graphical user interface, presenting data in a user-friendly manner rather than in their raw form. This interface should offer various visualization options, empowering users to choose representations that best convey the data and facilitate informed decision-making. Thus, this study aims to assess the potential of integrating social media into pharmacovigilance and enhancing decision-making with this novel data source. To achieve this, our objective was to develop and assess a pipeline that processes data from the extraction of web forum posts to the generation of indicators and alerts within a visual and interactive environment. The goal was to create a user-friendly tool that enables regulatory authorities to make better-informed decisions effectively.
METHODS
To enhance pharmacovigilance efforts, we have devised a pipeline comprising 4 distinct modules, each independently editable, aimed at efficiently analyzing health-related French web forums. These modules were (1) web forums' posts extraction, (2) web forums' posts annotation, (3) statistics and signal detection algorithm, and (4) a graphical user interface (GUI). We showcase the efficacy of the GUI through an illustrative case study involving the introduction of the new formula of Levothyrox in France. This event led to a surge in reports to the French regulatory authority.
RESULTS
Between January 1, 2017, and February 28, 2021, a total of 2,081,296 posts were extracted from 23 French web forums. These posts contained 437,192 normalized drug-ADE couples, annotated with the Anatomical Therapeutic Chemical (ATC) Classification and Medical Dictionary for Regulatory Activities (MedDRA). The analysis of the Levothyrox new formula revealed a notable pattern. In August 2017, there was a sharp increase in posts related to this medication on social media platforms, which coincided with a substantial uptick in reports submitted by patients to the national regulatory authority during the same period.
CONCLUSIONS
We demonstrated that conducting quantitative analysis using the GUI is straightforward and requires no coding. The results aligned with prior research and also offered potential insights into drug-related matters. Our hypothesis received partial confirmation because the final users were not involved in the evaluation process. Further studies, concentrating on ergonomics and the impact on professionals within regulatory agencies, are imperative for future research endeavors. We emphasized the versatility of our approach and the seamless interoperability between different modules over the performance of individual modules. Specifically, the annotation module was integrated early in the development process and could undergo substantial enhancement by leveraging contemporary techniques rooted in the Transformers architecture. Our pipeline holds potential applications in health surveillance by regulatory agencies or pharmaceutical companies, aiding in the identification of safety concerns. Moreover, it could be used by research teams for retrospective analysis of events.
Topics: Humans; Pharmacovigilance; Drug-Related Side Effects and Adverse Reactions; Social Media; Adverse Drug Reaction Reporting Systems; Internet
PubMed: 38888956
DOI: 10.2196/46176 -
Journal of Medicinal Chemistry Jun 2024Rheumatoid arthritis (RA) is a chronic autoimmune disease. Targeting NLRP3 inflammasome, specifically its interaction with NEK7 via the LRR domain of NLRP3, is a...
Rheumatoid arthritis (RA) is a chronic autoimmune disease. Targeting NLRP3 inflammasome, specifically its interaction with NEK7 via the LRR domain of NLRP3, is a promising therapeutic strategy. Our research aimed to disrupt this interaction by focusing on the LRR domain. Through virtual screening, we identified five compounds with potent anti-inflammatory effects and ideal LRR binding affinity. Lead compound underwent structural optimization, yielding pyridoimidazole derivatives with different anti-inflammatory activities. Compound from the initial series effectively inhibited caspase-1 and IL-1β release in an adjuvant-induced arthritis (AIA) rat model, significantly reducing joint swelling and spleen/thymus indices. To further enhance potency and extend half-life, a second series including was developed, demonstrating superior efficacy and longer half-life. Both and bind to the LRR domain, inhibiting NLRP3 inflammasome activation. These findings introduce novel small molecule inhibitors targeting the LRR domain of NLRP3 protein and disrupt NLRP3-NEK7 interaction, offering a novel approach for RA treatment.
Topics: NLR Family, Pyrin Domain-Containing 3 Protein; NIMA-Related Kinases; Animals; Arthritis, Rheumatoid; Humans; Rats; Arthritis, Experimental; Drug Discovery; Structure-Activity Relationship; Male; Inflammasomes; Molecular Docking Simulation; Antirheumatic Agents
PubMed: 38888047
DOI: 10.1021/acs.jmedchem.3c02407 -
Frontiers in Artificial Intelligence 2024Regulatory agencies generate a vast amount of textual data in the review process. For example, drug labeling serves as a valuable resource for regulatory agencies, such...
INTRODUCTION
Regulatory agencies generate a vast amount of textual data in the review process. For example, drug labeling serves as a valuable resource for regulatory agencies, such as U.S. Food and Drug Administration (FDA) and Europe Medical Agency (EMA), to communicate drug safety and effectiveness information to healthcare professionals and patients. Drug labeling also serves as a resource for pharmacovigilance and drug safety research. Automated text classification would significantly improve the analysis of drug labeling documents and conserve reviewer resources.
METHODS
We utilized artificial intelligence in this study to classify drug-induced liver injury (DILI)-related content from drug labeling documents based on FDA's DILIrank dataset. We employed text mining and XGBoost models and utilized the Preferred Terms of Medical queries for adverse event standards to simplify the elimination of common words and phrases while retaining medical standard terms for FDA and EMA drug label datasets. Then, we constructed a document term matrix using weights computed by Term Frequency-Inverse Document Frequency (TF-IDF) for each included word/term/token.
RESULTS
The automatic text classification model exhibited robust performance in predicting DILI, achieving cross-validation AUC scores exceeding 0.90 for both drug labels from FDA and EMA and literature abstracts from the Critical Assessment of Massive Data Analysis (CAMDA).
DISCUSSION
Moreover, the text mining and XGBoost functions demonstrated in this study can be applied to other text processing and classification tasks.
PubMed: 38887604
DOI: 10.3389/frai.2024.1401810 -
Frontiers in Pharmacology 2024With the continuously increasing incidence of type 2 diabetes, glucagon-like peptide-1 (GLP-1) receptor agonists, known for their dual benefits of effectively...
BACKGROUND
With the continuously increasing incidence of type 2 diabetes, glucagon-like peptide-1 (GLP-1) receptor agonists, known for their dual benefits of effectively controlling blood glucose levels while also reducing weight and lowering cardiovascular disease risks, have been widely employed in the treatment of this condition. In recent years, semaglutide has garnered significant attention as the only injectable and orally administered glucagon-like peptide-1 receptor agonist (GLP-1RA). However, it is important to note that different routes of administration may lead to varying adverse events in patients. The aim of this study is to compare the adverse event profiles of semaglutide across different routes of administration by analyzing the adverse event reporting system of the U.S. Food and Drug Administration (FDA). The findings from this analysis will provide valuable insights for clinical practice and drug surveillance.
METHODS
Data was extracted from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, specifically focusing on the period from the fourth quarter of 2017 to the fourth quarter of 2023. A comparative analysis was conducted using disproportionality analysis, reporting odds ratio (ROR), and stratified analysis methods to assess and compare the signals of adverse events (AE) and the time to onset of adverse reactions associated with different routes of administration of semaglutide from 2017 to 2023.
RESULTS
A total of 22,287 adverse reaction records related to semaglutide were identified in the FAERS database. A comparative analysis was performed on 16,346 records of subcutaneous administration and 2,496 records of oral administration. Different routes of administration can lead to varying adverse reaction outcomes. Compared to oral administration, subcutaneous injection is more likely to result in adverse events related to the endocrine system. Oral administration is more likely to induce adverse events in the gastrointestinal system. Additionally, it significantly accelerates the onset of adverse reactions. The comparative analysis of all relevant results indicates that semaglutide can lead to different adverse reaction events depending on the route of administration. Furthermore, there are significant differences in the time of onset for these adverse reactions.
CONCLUSION
Semaglutide exhibits variations in adverse reaction events and the time of onset across different routes of administration. Therefore, when selecting the route of administration for semaglutide, clinicians should consider the risk of adverse events and weigh them against the clinical benefits. Based on these considerations, appropriate guidance and recommendations can be provided to patients.
PubMed: 38887555
DOI: 10.3389/fphar.2024.1414268 -
BMC Medicine Jun 2024Most women use medication during pregnancy. Pregnancy-induced changes in physiology may require antenatal dose alterations. Yet, evidence-based doses in pregnancy are...
BACKGROUND
Most women use medication during pregnancy. Pregnancy-induced changes in physiology may require antenatal dose alterations. Yet, evidence-based doses in pregnancy are missing. Given historically limited data, pharmacokinetic models may inform pregnancy-adjusted doses. However, implementing model-informed doses in clinical practice requires support from relevant stakeholders.
PURPOSE
To explore the perceived barriers and facilitators for model-informed antenatal doses among healthcare practitioners (HCPs) and pregnant women.
METHODS
Online focus groups and interviews were held among healthcare practitioners (HCPs) and pregnant women from eight countries across Europe, Africa and Asia. Purposive sampling was used to identify pregnant women plus HCPs across various specialties prescribing or providing advice on medication to pregnant women. Perceived barriers and facilitators for implementing model-informed doses in pregnancy were identified and categorised using a hybrid thematic analysis.
RESULTS
Fifty HCPs and 11 pregnant women participated in 12 focus groups and 16 interviews between January 2022 and March 2023. HCPs worked in the Netherlands (n = 32), the UK (n = 7), South Africa (n = 5), Uganda (n = 4), Kenya, Cameroon, India and Vietnam (n = 1 each). All pregnant women resided in the Netherlands. Barriers and facilitators identified by HCPs spanned 14 categories across four domains whereas pregnant women described barriers and facilitators spanning nine categories within the same domains. Most participants found current antenatal dosing information inadequate and regarded model-informed doses in pregnancy as a valuable and for some, much-needed addition to antenatal care. Although willingness-to-follow model-informed antenatal doses was high across both groups, several barriers for implementation were identified. HCPs underlined the need for transparent model validation and endorsement of the methodology by recognised institutions. Foetal safety was deemed a critical knowledge gap by both groups. HCPs' information needs and preferred features for model-informed doses in pregnancy varied. Several pregnant women expressed a desire to access information and partake in decisions on antenatal dosing.
CONCLUSIONS
Given the perceived limitations of current pharmacotherapy for pregnant women and foetuses, model-informed dosing in pregnancy was seen as a promising means to enhance antenatal care by pregnant women and healthcare practitioners.
Topics: Humans; Female; Pregnancy; Qualitative Research; Focus Groups; Health Personnel; Pregnant Women; Adult; Prenatal Care; Africa; Asia; Europe; Uganda
PubMed: 38886762
DOI: 10.1186/s12916-024-03450-8