Optimization of oral isavuconazole dose for population in special physiological or pathological state: a physiologically based pharmacokinetics model-informed precision dosing.

OBJECTIVE: To recommend precision dosing and improve therapeutic efficacy against invasive fungal disease, a physiologically based pharmacokinetic model (PBPK) of oral isavuconazole (ISA) was established and used to explore its disposition across populations in different physiological and pathological states. METHODS: Twenty-five pharmacokinetic (PK) studies of oral ISA were identified through a systematic search of PubMed. Concentration-time data were extracted using WebPlotDigitizer. Physiochemical parameters were obtained from published literature and DrugBank. Model development and simulation used the Simcyp population-based simulator, and visual predictive check and predictive error were used for the model evaluation. Probability of target attainment and the cumulative fraction of response analyses were performed for dose optimization. RESULTS: The developed PBPK model was successfully validated in different populations. Most predicted concentration-time points aligned with the observed data, with acceptable predictive errors for the critical parameters. We predicted the PK profiles and parameters of ISA in a population with severe hepatic impairment (HI), a population with obesity and paediatric patients aged 1 to less than 6 years old. The probability of target attainment and cumulative fraction of response analyses indicated that the population with severe HI should have half the maintenance dose. The population with obesity and population with severe HI should have a loading dose of 300 mg every 8 h for 2 days. For paediatric patients aged 1 to less than 6 years old, a weight-based dosing regimen (5.38 mg/kg) of ISA was suggested. CONCLUSION: The predicted value aligns with observations, suggesting ISA's potential predictability in PK profiles for other populations. The recommended dosing regimens increase our understanding of the use of ISA in special populations.

Multiple Adverse Reactions Associated With the Use of Second-Generation Antipsychotics in People With Alzheimer's Disease: A Pharmacovigilance Analysis Based on the FDA Adverse Event Reporting System.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition leading to memory loss, cognitive impairment, and neuropsychiatric symptoms. Second-generation antipsychotics (SGAs) are commonly used to manage these neuropsychiatric symptoms, but their safety profile in patients with AD requires further investigation. OBJECTIVE: The objective was to evaluate the safety of SGAs in patients with AD by analyzing adverse drug reactions (ADRs) using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: This study conducted a comprehensive analysis of FAERS data from 2014 to 2023, focusing on ADRs in patients with AD treated with SGAs such as risperidone, quetiapine, olanzapine, clozapine, and aripiprazole. Descriptive, disproportionality, time, and dose analysis were performed using the Bayesian confidence propagation neural network, Weibull, and physiologically based pharmacokinetic model. RESULTS: Out of 1289 patients with AD treated with SGAs, the most common ADRs involved the nervous system, gastrointestinal system, and cardiac disorders. Disproportionality analysis identified significant positive signals in cardiac, renal, and vascular systems. Quetiapine, risperidone, and olanzapine showed more positive signals compared with clozapine and aripiprazole. Time analysis indicated that cardiovascular ADRs occurred randomly, whereas renal ADRs increased with prolonged use. Dose analysis suggested that small doses of SGAs did not elevate the risk of multiple cardiac, renal, or vascular ADRs. CONCLUSION AND RELEVANCE: The study underscores the importance of monitoring for ADRs, particularly in the cardiac and renal systems, when using SGAs in patients with AD. Future research incorporating more comprehensive clinical data is warranted to support safe and rational drug utilization.

Exploring the Link Between Exogenous Thyroid Hormones and Dementia Symptoms: A Real-World Disproportionality Analysis of FDA Adverse Event Reporting System.

BACKGROUND: A growing body of evidence indicates a strong association between exogenous thyroid hormone (ETH) and brain health. Establishing the potential relationship between ETH therapy and dementia symptoms is crucial for patients with thyroid disorders. OBJECTIVE: In this study, we investigate the potential association between ETH therapy and dementia symptoms by exploring the Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: Disproportionality analysis (DPA) was conducted using postmarketing data from the FAERS repository (Q1 2004 to Q4 2023). Cases of dementia symptoms associated with ETH therapy were identified and analyzed through DPA using reporting odds ratios and information component methods. Dose and time-to-onset analyses were performed to assess the association between ETH therapy and dementia symptoms. RESULTS: A total of 9889 cases of ETH-associated symptoms were identified in the FAERS database. Dementia accounted for a consistent proportion of adverse drug reactions each year (3.4%-6.3%). The DPA indicated an association between ETH therapy and dementia symptoms, which remained significant even across sex, age, and indications. The median time-to-onset of dementia symptoms was 7.5 days, and the median treatment time was 40.5 days. No significant dose-response relationship was observed. CONCLUSION AND RELEVANCE: This study provides evidence for a link between ETH therapy and dementia. Clinicians are therefore advised to exercise vigilance, conduct comprehensive monitoring, and consider individualized dosing to mitigate potential reactions to ETH drug administration.

Movement disorders associated with antiseizure medications: A real-world disproportionality analysis of the Food and Drug Administration Adverse Event Reporting System.

AIMS: Patients with epilepsy often require long-term use of antiseizure medications (ASMs) to control their seizures. However, movement disorders (MDs) related to ASMs can significantly impact their quality of life. This study aims to analyse MDs related to ASMs in the Food and Drug Administration Adverse Event Reporting System database to provide recommendations for safe medication. METHODS: All adverse drug reactions associated with 26 marketed ASMs in Food and Drug Administration Adverse Event Reporting System were extracted for analysis. Disproportionality analyses were used to assess the association between ASMs and MDs, and signal colour scale maps were created to identify potential ASM-MD safety signals. RESULTS: A total of 1921 cases experienced MDs while taking ASMs were included. A higher prevalence of MDs was observed in females compared to males. The association between specific MDs with ASMs was revealed, including known and unknown MDs such as tremors, Parkinson and paralysis. Lamotrigine and carbamazepine exhibited multiple significant MDs, while levetiracetam and pregabalin were linked to the earlier onset of MDs. Generally, higher doses were linked to a higher incidence of MDs. CONCLUSION: MDs were the most obvious adverse drug reactions in the nervous system triggered by using ASMs. Fourteen drugs exhibited positive signals for MDs, including some not previously reported. Conversely, 12 ASMs were deemed to have a lower possibility of inducing MDs. The incidence of MDs can be mitigated by selecting appropriate ASMs for epileptic patients. These findings enhance our understanding of the relationship between ASMs and MDs.

Disproportionality Analysis of Lenvatinib-Caused Gastrointestinal Perforation in Cancer Patients: A Pharmacovigilance Analysis Based on the US Food and Drug Administration Adverse Event Reporting System.

Lenvatinib is a medication that targets multiple tyrosine kinases and is commonly used to treat various types of cancer. With its frequent usage, monitoring and assessing its potential adverse effects has become crucial. This study utilizes the US Food and Drug Administration Adverse Event Reporting System (FAERS) database to analyze the possible link between lenvatinib and gastrointestinal perforation. FAERS was used to analyze adverse drug reactions (ADRs) linked with lenvatinib from the first quarter of 2015 to the last quarter of 2022. The association between lenvatinib and gastrointestinal perforation was evaluated using disproportionality analyses. This study included 464 patients who developed gastrointestinal perforation after using lenvatinib. Perforation involved the entire digestive tract, with the colon among the most commonly affected perforation sites, and previously undetected esophageal perforation was frequently observed. Patients with uterine and liver cancer were at a higher risk of developing gastrointestinal perforation; patients with liver cancer experienced a shorter onset time, whereas patients with endometrial cancer had a slower onset time. Middle-aged and elderly patients exhibited a higher propensity for developing gastrointestinal perforation than younger adults. Patients with gastrointestinal perforation were found to have a significantly higher mortality rate than patients without gastrointestinal perforation. This study has identified several gastrointestinal perforation events not included in the drug instructions. It has also described the perforation site and clinical characteristics based on various types of cancer. These results could provide valuable insights for developing safer and more effective regulatory strategies concerning the use of lenvatinib.

Pharmacovigilance of triazole antifungal agents: Analysis of the FDA adverse event reporting system (FAERS) database.

Triazole antifungal drugs (TAD) are widely used to treat invasive fungal infections due to their broad antifungal spectrum and low toxicity. Despite their preference in the clinic, multiple Adverse Events (AE) are still reported each year. OBJECTIVE: We aimed to characterize the distribution of Adverse Events associated with Triazole antifungal drugs in different systems and to identify Important Medical Events (IME) signals for Triazole antifungal drugs. METHODS: The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) was queried for Adverse Events related to Triazole antifungal drugs from 2012 to 2022. The Adverse Events caused by all other drugs and non-TAD antifungal drugs were analyzed as references. Reporting odds ratio and Bayesian confidence propagation neural network of information components were used to evaluate the association between Triazole antifungal drugs and Important Medical Events. Visual signal spectrum is mapped to identify potential adverse reaction signals. RESULTS: Overall, 10,262 Adverse Events were reported to be associated with Triazole antifungal drugs, of which 5,563 cases were defined as Important Medical Events. Common adverse drug reactions (ADR) mentioned in the instructions such as delirium and hypokalemia were detected, as well as unlabeled ADRs such as rhabdomyolysis and hepatitis fulminant. Cholestasis, drug-induced liver injury, QT interval prolongation and renal impairment have notable signals in all Triazole antifungal drugs, with 50 percent of patients developing a severe clinical outcome. Isavuconazole had the lowest signal intensity and demonstrated a superior safety profile. CONCLUSION: Most results are generally consistent with previous studies and are documented in the prescribing instructions, but some IMEs are not included, such as hepatitis fulminant. Additional pharmaco-epidemiological or experimental studies are required to validate the small number of unlabeled ADRs. TAD-related Important Medical Eventshave a considerable potential to cause clinically serious outcomes. Clinical use of Triazole antifungal drugs requires more attention.

Tunable construction of multi-shelled hollow carbonate nanospheres and their potential applications.

The development of multi-shelled hollow carbonate nanospheres (MHCN) for biomedical applications is challenging, and has not been reported. In this study, a facile approach is firstly reported to synthesize hierarchically porous MHCN with controllable shell numbers using a novel strategy called layer-by-layer thermal decomposition of organic acid salts and templates. The choice of organic acid salts as the reactants is innovative and crucial. The shell numbers of porous MHCN can be easily controlled and tuned through adjusting the adsorption temperature of organic acid salts and/or the adsorption ability of the template. The synthetic method can not only open a window to prepare the multi-shelled carbonates but also provide a new strategy to synthesise other multi-shelled inorganic salts. Notably, the hierarchically porous multi-shelled hollow structures empower the carbonates with not only a large specific surface area but also good porosity and permeability, showing great potential for future applications. Herein, our in vitro/vivo evaluations show that CaCO3 MHCN possess a high drug loading capacity and a sustained-release drug profile. It is highly expected that this novel synthetic strategy for MHCN and novel MHCN platform have the potential for biomedical applications in the near future.