Search

Abstract Combining the FDA Adverse Event Reporting System (FAERS) and the Cancer Genome Atlas (TCGA) databases, we aim to explore the factors that influence anti-programmed cell death protein-1 inhibitors/programmed death-ligand-1 (PD-1/PD-L1) related severe cardiac adverse events (cAEs). We obtained anti-PD-1/PD-L1 adverse event reports from January 2014 to December 2022 from the FAERS database. Disproportionality analysis was performed to find anti-PD-1/PD-L1-related cAEs using the proportional reporting ratio (PRR). We were exploring influencing factors based on multivariate logistic regression analysis. Finally, we utilized a strategy that combines FAERS and TCGA databases to explore the potential immune and genetic influencing factors associated with anti-PD-1/PD-L1-related severe cAEs. Reports of severe cAEs accounted for 7.10% of the overall anti-PD-1/PD-L1 adverse event reports in the FAERS database. Immune-mediated myocarditis (PRR = 77.01[59.77–99.23]) shows the strongest toxic signal. The elderly group (65–74: OR = 1.34[1.23–1.47], ≥ 75: OR = 1.64[1.49–1.81]), male (OR = 1.14[1.05–1.24]), anti-PD-L1 agents (OR = 1.17[1.03–1.33]), patients with other adverse events (OR = 2.38[2.17–2.60]), and the concomitant use of proton pump inhibitor (OR = 1.29[1.17–1.43]), nonsteroidal anti-inflammatory drugs (OR = 1.17[1.04–1.31]), or antibiotics (OR = 1.24[1.08–1.43]) may increase the risk of severe cAEs. In addition, PD-L1 mRNA (Rs = 0.71, FDR = 2.30 × 10− 3) and low-density lipoprotein receptor-related protein 3 (LRP3) (Rs = 0.82, FDR = 2.17 × 10− 2) may be immune and genetic influencing factors for severe cAEs. Severe cAEs may be related to antigen receptor-mediated signalling pathways. In this study, we found that age, gender, anti-PD-1/PD-L1 agents, concomitant other adverse events, concomitant medication, PD-L1 mRNA, and LRP3 may be influencing factors for anti-PD-1/PD-L1-related severe cAEs. However, our findings still require a large-scale prospective cohort validation.

Abstract Background Oral aripiprazole exhibits favorable clinical efficacy and safety in the suppression of tics in children and adolescents with tic disorders. This study aims to evaluate and compare the cost-effectiveness of high-dose and low-dose aripiprazole in children and adolescents with tic disorders from the perspective of the Chinese healthcare system. Methods A questionnaire survey was conducted on 146 patients with tic disorders, of whom 144 completed EQ-5D-Y and YGTSS. Four models were built to convert YGTSS onto EQ-5D-Y utility using two mapping algorithms. We constructed a decision tree model containing efficacy and safety to compare the cost-effectiveness of high-dose and low-dose aripiprazole based on our mapping function. Results The GLM with model 1 (YGTSS total tic scores) was selected as the preferred function in our decision tree model. The base case cost-effectiveness analysis showed that compared to low-dose aripiprazole, high-dose aripiprazole improves effectiveness by 0.001QALYs and increases the overall cost by $197.99, resulting in an ICER of $174339.22 per QALY, which exceeds three times the gross domestic product per capita. Hence, high-dose aripiprazole is not likely to be a cost-effective option for child patients with tic disorders. One-way sensitivity analysis and probabilistic sensitivity analysis showed that these results is robust. Conclusion On the basis of currently available data, low-dose aripiprazole may be a safe, effective, and economical dosage for children and adolescents with tic disorders. Limitations The main limitation of our study is the lack of utility directly used for cost-effectiveness analysis. We obtained the utility of patients with tic disorders indirectly by the mapping function. This may introduce some bias and uncertainty. And it is a limitation to use the direct medical costs of Germany in our model. Although we converted it to the equivalent value of China using purchasing power parities, caution should be exercised when interpreting the results of this study.

Introduction: Chronic hepatitis B (CHB) is a worldwide infectious disease caused by hepatitis B virus (HBV). Optimizing antiviral treatment strategies could improve the functional cure (FC) rate of patients with CHB. This study aims to systematically review the FC rate of the de novo combination of nucleos(t)ide analogs (NAs) and pegylated interferon α (PEG-IFNα) versus that of PEG-IFNα monotherapy for CHB.Methods: Databases were searched until 31 December 2023. Selected studies included randomized controlled trials on the de novo combination of NAs and PEG-IFNα versus PEG-IFNα monotherapy for 48 weeks in patients with CHB to achieve FC, which was defined as hepatitis B surface antigen (HBsAg) loss and/or HBsAg seroconversion. Meta-analysis was conducted in accordance with the efficacy at the end of treatment and different time points during follow-up.Results: A total of 10 studies, encompassing 2,339 patients in total, were included. Subgroup analysis was conducted in accordance with whether first-line NAs were used. It found no statistically significant difference between HBsAg loss and HBsAg seroconversion at the end of treatment. Serum HBV DNA

Abstract Background Establishing whether there is a potential relationship between glucagon-like peptide 1 receptor agonists (GLP-1RAs) and suicidal or self-injurious behaviors (SSIBs) is crucial for public safety. This study investigated the potential association between GLP-1RAs and SSIBs by exploring the FDA Adverse Event Reporting System (FAERS) database. Methods A disproportionality analysis was conducted using post-marketing data from the FAERS repository (2018 Q1 to 2022 Q4). SSIB cases associated with GLP-1RAs were identified and analyzed through disproportionality analysis using the information component. The parametric distribution with a goodness-of-fit test was employed to analyze the time-to-onset, and the Ω shrinkage was used to evaluate the potential effect of co-medication on the occurrence of SSIBs. Results In total, 204 cases of SSIBs associated with GLP-1RAs, including semaglutide, liraglutide, dulaglutide, exenatide, and albiglutide, were identified in the FAERS database. Time-of-onset analysis revealed no consistent mechanism for the latency of SSIBs in patients receiving GLP-1RAs. The disproportionality analysis did not indicate an association between GLP-1RAs and SSIBs. Co-medication analysis revealed 81 cases with antidepressants, antipsychotics, and benzodiazepines, which may be proxies of mental health comorbidities. Conclusions We found no signal of disproportionate reporting of an association between GLP-1RA use and SSIBs. Clinicians need to maintain heightened vigilance on patients premedicated with neuropsychotropic drugs. This contributes to the greater acceptance of GLP-1RAs in patients with type 2 diabetes mellitus or obesity. Graphical Abstract

Abstract Background Immune checkpoint inhibitors (ICIs) have transformed tumor treatment. However, the risk of pulmonary adverse events (PAEs) associated with ICI combination therapy is still unclear. We aimed to provide a PAE overview and risk ordering of ICIs used in tumor treatment. Methods We searched the databases of PubMed, PsycINFO, Embase, Cochrane Library, CINAHL, Web of Science, Scopus, and clinical trial websites during January 2011–April 2023 to identify phase II and III randomized clinical trials (RCTs) and single-arm clinical trials wherein at least one treatment arm received ICIs (e.g., ICI monotherapy, a combination of two ICIs, or ICIs in combination with conventional cancer therapy). We reported the results of PAEs. Additionally, we compared risks of PAEs between different drug classes using a Bayesian network meta-analysis. Results Among 143 RCTs and 24 single-arm trials, the incidence of all-grade and grade 3–4 PAEs were highest with programmed death L1 (PD-L1) plus cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and plus chemotherapy and anti-PD1 plus anti-CTLA4, the lowest with targeted therapy drug plus chemotherapy and anti-PD1 plus anti-PDL1. Anti-PD1 plus anti-CTLA4 and plus chemotherapy was the intervention with the highest risk for all-grade and 3–4 grade PAEs, and the intervention with the lowest risk was chemotherapy and anti-PD1 plus anti-PDL1. In terms of all-grade PAEs, chemotherapy was safer than ICI monotherapy. Except for the anti-PD1 plus anti-PDL1 regimen, no significant difference in the risk of grade 3–4 PAEs was detected between dual-ICIs and single-ICIs. Furthermore, the risk of PAEs associated with nivolumab, pembrolizumab, and atezolizumab may be dose dependent. Conclusions In the single-drug regimen, anti-PD1 caused the greatest incidence of PAEs. The risk of PAEs was higher with all single-ICIs than with chemotherapy. However, no significant difference in the risk of PAEs was detected between single-ICIs. In the combined regimen, anti-PD1 plus anti-CTLA4 and plus chemotherapy showed the greatest risk of PAEs, but there were no significant differences in risk between dual-ICIs and single-ICIs.

Abstract Therapeutic drug monitoring (TDM) of busulfan (BU) is currently performed by plasma sampling in patients undergoing hematopoietic stem cell transplantation (HSCT). Saliva samples are considered a noninvasive TDM matrix. Currently, no salivary population pharmacokinetics (PopPKs) model for BU available. This study aimed to develop a PopPK model that can describe the relationship between plasma and saliva kinetics in patients receiving intravenous BU. The performance of the model in predicting the area under the concentration‐time curve at steady state (AUCss) based on saliva samples is evaluated. Sixty‐six patients with HSCT were recruited and administered 0.8 mg/kg BU intravenously. A PopPK model for saliva and plasma was developed using the nonlinear mixed effects model. Bayesian maximum a posteriori (MAP) optimization was used to estimate the model's predictive performance. Plasma and saliva PKs were adequately described with a one‐compartment model and a scaled central compartment. Body surface area correlated positively with both clearance and apparent volume of distribution (Vd), whereas alkaline phosphatase correlated negatively with Vd. Simulations demonstrated that the percentage root mean squared prediction error and lower and upper limits of agreements reduced to 10.02% and −16.96% to 22.86% based on five saliva samples. Saliva can be used as an alternative matrix to plasma in TDM of BU. The AUCss can be predicted from saliva concentration by Bayesian MAP optimization, which can be used to design personalized dosing for BU.

Abstract Background Immune‐related pneumonitis is a rare and potentially fatal adverse event associated with sintilimab. We aimed to develop and validate a nomogram for predicting the risk of immune‐related pneumonitis in patients treated with sintilimab. Methods The least absolute shrinkage and selection operator (LASSO) regression was used to determine risk factors. Multivariable logistic regression was used to establish a prediction model. Its clinical validity was evaluated using calibration, discrimination, decision, and clinical impact curves. Internal validation was performed against the validation set and complete dataset. Results The study included 632 patients; 59 were diagnosed with immune‐related pneumonitis. LASSO regression analysis identified that the risk factors for immune‐related pneumonitis were pulmonary metastases (odds ratio [OR], 4.015; 95% confidence interval [CI]: 1.725–9.340) and metastases at >3 sites (OR, 2.687; 95% CI: 1.151–6.269). The use of combined antibiotics (OR, 0.247; 95% CI: 0.083–0.738) and proton pump inhibitors (OR, 0.420; 95% CI: 0.211–0.837) were protective factors. The decision and clinical impact curves showed that the nomogram had clinical value for patients treated with sintilimab. Conclusions We have developed and validated a practical nomogram model of sintilimab‐associated immune‐related pneumonitis, which provides clinical value for determining the risk of immune‐related pneumonitis and facilitating the safe administration of sintilimab therapy.

BackgroundThis study evaluated the cost-effectiveness of elacestrant (ELA) and standard-of-care (SOC) as second-/third-line treatment for pretreated estrogen receptor (ER)– positive/human epidermal growth factor receptor 2 (HER2)–negative advanced or metastatic breast cancer (A/MBC) in the US.MethodsThe 3 health states partitioned survival model (PSM) was conducted from the perspective of the US third-party payers. The time horizon for the model lasted 10 years. Effectiveness and safety data were derived from the EMERALD trial (NCT03778931). Costs were derived from the pricing files of Medicare and Medicaid Services, and utility values were derived from published studies. One-way sensitivity analysis as well as probabilistic sensitivity analysis were performed to observe model stability.ResultELA led to an incremental cost-effectiveness ratio (ICER) of $8,672,360/quality-adjusted life year (QALY) gained compared with SOC in the overall population and $2,900,560/QALY gained compared with fulvestrant (FUL) in the ESR1(estrogen receptor 1) mutation subgroup. The two ICERs of ELA were significantly higher than the willingness-to-pay (WTP) threshold values of $150,000/QALY.ConclusionsELA was not cost-effective for the second-/third-line treatment of patients with ER+/HER2–A/MBC compared with SOC in the US.

Background: Axicabtagene ciloleucel (Axi-cel) is the first Chimeric Antigen Receptor T-Cell Immunotherapy (CAR-T) product approved in China for treating adult patients with relapsed or refractory large B-cell lymphoma after receiving second-line or above systemic therapy. However, it cannot be widely used in clinical practice due to its high price. Objectives: To evaluate the economic value of Axi-cel fully in countries at different stages of economic development, this article, from the perspective of the medical and health system in China and the United States, evaluated the cost-effectiveness of Axi-cel in the second-line treatment of diffuse large B-cell lymphoma (DLBCL). Design: Cost effectiveness analysis of Axi-cel in the treatment of relapsed or refractory large B-cell lymphoma (LBCL). Methods: Based on the clinical trial data of ZUMA-7, a short-term decision tree and a long-term semi-Markov partitioned survival model were constructed to evaluate the cost-effectiveness of the two strategies. This model was cycled for 40 years in 1-month cycles. In this article, only direct medical costs were considered. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted to assess the robustness of the base-case results. Results: In the baseline cost-effectiveness analysis, Axi-cel was associated with more quality-adjusted life year (QALY; 2.72 versus 1.46) and greater costs overall ($180,501.55 versus $123,221.34) than standard second-line chemotherapy in China. Moreover, the incremental cost-effectiveness ratio (ICER) of the Axi-cel group was $45,726.66/QALY, which was greater than the threshold of $37,654.5. To achieve cost-effectiveness, the price of Axi-cel must be reduced appropriately. In the United States, Axi-cel was associated with more QALYs (2.63 versus 1.74) and greater costs overall ($415,915.16 versus $289,564.34). The ICER for the Axi-cel was $142,326.94/QALY, below the set threshold of $150,000. Conclusion: Axi-cel is not a cost-effective option as second-line therapy for treating DLBCL in China. However, In the United States, Axi-cel has shown a cost-effectiveness advantage as a second-line treatment for DLBCL.

Background: The CheckMate-649 trial compared nivolumab plus chemotherapy (NC) with chemotherapy alone as first-line treatment for advanced gastric cancer (GC), gastroesophageal junction cancer (GEJC), and esophageal adenocarcinoma (EAC) and showed significant benefits to progression-free survival and overall survival. This study evaluated the lifetime cost-effectiveness of NC versus chemotherapy alone in patients with GC/GEJC/EAC from the perspective of the US payers. Methods: A 10-year partitioned survival model was constructed to evaluate the cost-effectiveness of NC and chemotherapy alone and measured the health achievements in quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and life-years. Health states and transition probabilities were modeled from the survival data from the CheckMate-649 clinical trial (NCT02872116). Only direct medical costs were considered. One-way and probabilistic sensitivity analyses were conducted to assess the robustness of the results. Results: On comparing the chemotherapy, we found that NC incurred substantial health costs, resulting in ICERs of $240,635.39/QALY, $434,182.32/QALY, and $386,715.63/QALY for the model of patients with programmed cell death-ligand 1 (PD-L1) combined positive score (CPS) ⩾5, PD-L1 CPS ⩾1, and all-treated patients, respectively. All ICERs were significantly higher than the willingness-to-pay threshold value of $150,000/QALY. The main influencing factors were the cost of nivolumab, the utility value of the progression-free disease, and the discount rate. Conclusion: Compared with chemotherapy alone, NC may not be a cost-effective option for treating advanced GC, GEJC, and EAC in the United States.

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.

Introduction: The role of bevacizumab combined with paclitaxel and carboplatin in the first-line treatment of advanced non-squamous non-small-cell lung cancer (NSCLC) has been supported by a large number of data. However, whether bevacizumab biosimilars have the same efficacy and safety as the original drug is still controversial. This meta-analysis was designed to evaluate whether bevacizumab biosimilars have the same clinical efficacy and safety as the original drug in patients with advanced non-squamous NSCLC. Methods: Electronic databases (PubMed, Embase, Cochrane, CNKI, Wanfang, and VIP) and the ClinicalTrail.gov website were extensively searched using relevant search criteria. We included phase III randomized controlled trials (RCTs) to compare the efficacy and safety of marketed biosimilars and Avastin in the first-line treatment of patients with advanced NSCLC. The risk of bias of the included studies was assessed using the RoB 2 assessment scale, and the RevMan 5.4 statistical software was used for meta-analysis. Results: A total of 6360 patients were included in 11 RCTs. There was no statistical difference between the experimental group and the control group in terms of effectiveness [objective response rate (at week 18), disease control rate (at week 18), median duration of response, median progression-free survival, median overall survival (OS), and OS after 12 months]. In terms of safety [treatment-emergent adverse events (grade ⩾3) and treatment-related adverse events (grade ⩾3)], there was also no significant difference between biosimilars and Avastin. Conclusions: The efficacy and safety of bevacizumab biosimilars in the treatment of advanced non-squamous NSCLC are highly similar to those of the original drug combined with paclitaxel and carboplatin, respectively.

Background: This study evaluated the cost-effectiveness of nivolumab plus chemotherapy (NC) or ipilimumab versus chemotherapy as a first-line treatment for advanced esophageal squamous cell carcinoma (ESCC) in the United States and China. Methods: A partitioned survival model was constructed from the perspective of the US third-party payers and Chinese healthcare system. Health states and transition probabilities were modeled based on the survival data from the CheckMate-648 clinical trial (NCT03143153). The time horizon for the model was 10 years. Only direct medical costs were considered. One-way and probabilistic sensitivity analyses were conducted to assess the robustness of the results. Results: In the United States, nivolumab plus ipilimumab (NI) led to an incremental cost-effectiveness ratio (ICER) of $155,159.82/quality-adjusted life year (QALY) and $104,297.07/QALY gained in the overall population and in patients with tumor cell programmed death-ligand 1 (PD-L1) expression of ⩾1% (subgroup), respectively. The ICER for the subgroup was between the willingness-to-pay (WTP) threshold values of $100,000/QALY and $150,000/QALY, and the other case was higher than $150,000/QALY. NC led to an ICER of $518,062.85/QALY and $193,169.49/QALY gained in the overall population and the subgroup, respectively. Both ICERs were significantly higher than the WTP threshold of $150,000/QALY. In China, the ICERs for patients treated with the addition of nivolumab were >$90,000/QALY in all cases, significantly exceeding the WTP threshold of $37,654/QALY. Conclusions: NI is more cost-effective than NC or chemotherapy alone for treating advanced ESCC with PD-L1 expression ⩾1% in the United States. Chemotherapy alone is the only cost-effective option in China.

Immune checkpoint inhibitors (ICIs) in combination withother anti-cancer treatments have been approved for a variety of cancers. While the difference in the incidence of cardiovascular adverse events has not been fully investigated. We aimed to assess the the differences in cardiotoxicity among cancer patients receiving different ICI therapies. PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov. websites were searched for all randomized controlled trials (RCTs) of ICI. The primary outcomes were any grade cardiotoxicity and Grade 3-5 cardiotoxicity, the secondary outcomes were any grade myocarditis and Grade 3-5 myocarditis, with sub-analyses based on cancer type and does of ICI. A systematic review and frequency network meta-analysis were then performed for cardiotoxicity events. 91 RCTs (n=52247) involving 12 treatment arms were finally included. We observed that PD-L1 + CTLA-4 had the highest risk among all therapies inducing any grade cardiotoxicity, and the differences were significant except PD-1 + CTLA-4, PD-1 + TTD and PD-L1 + TTD. In addition, CTLA-4 had a higher risk of Grade 3-5 cardiotoxicity than PD-1 and anit-PD-L1. For Grade 1-5 myocarditis and Grade 3-5 myocarditis, no significant difference was found among differences therapies. No differences were observed in subgroup analyses according to does and cancer type. There were differences in the incidence of cardiotoxicity among different ICI therapies. For ICI monotherapy, CTLA-4 may be linked to Grade 3-5 cardiotoxicity than PD-1 or PD-L1. For dual therapy, the cardiotoxicity of dual ICI therapy seems to be higher than that of chemotherapy or targeted therapy.

BackgroundPatients undergoing heart surgery may experience a range of physiological changes, and the postoperative recovery time is long. Patients and their families often have concerns about quality of life (QoL) after discharge. eHealth interventions may improve patient participation, ensure positive and effective health management, improve the quality of at-home care and the patient's quality of life, and reduce rates of depression. ObjectiveThe purpose of this study was to evaluate the effects of eHealth interventions on the physiology, psychology, and compliance of adult patients after cardiac surgery to provide a theoretical basis for clinical practice. MethodsWe conducted systematic searches of the following 4 electronic databases: PubMed, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials. Mean (SD) values were used to calculate the pooled effect sizes for all consecutive data, including QoL, anxiety, and depression. Where the same results were obtained using different instruments, we chose the standardized mean difference with a 95% CI to represent the combined effect size; otherwise, the mean difference (MD) with a 95% CI was used. Odds ratios were used to calculate the combined effect size for all dichotomous data. The Cohen Q test for chi-square distribution and an inconsistency index (I2) were used to test for heterogeneity among the studies. We chose a fixed-effects model to estimate the effect size if there was no significant heterogeneity in the data (I2≤50%); otherwise, a random-effects model was used. The quality of the included studies was assessed using the Cochrane risk-of-bias tool for randomized trials (RoB 2). ResultsThe search identified 3632 papers, of which 19 met the inclusion criteria. In terms of physical outcomes, the score of the control group was lower than that of the intervention group (MD 0.15, 95% CI 0.03-0.27, I2=0%, P=.02). There was no significant difference in the mental outcomes between the intervention and control groups (MD 0.10, 95% CI –0.03 to 0.24, I2=46.4%, P=.14). The control group’s score was lower than that of the intervention group for the depression outcomes (MD –0.53, 95% CI –0.89 to –0.17, I2=57.1%, P=.004). Compliance outcomes improved in most intervention groups. The results of the sensitivity analysis were robust. Nearly half of the included studies (9/19, 47%) had a moderate to high risk of bias. The quality of the evidence was medium to low. ConclusionseHealth improved the physical component of quality of life and depression after cardiac surgery; however, there was no statistical difference in the mental component of quality of life. The effectiveness of eHealth on patient compliance has been debated. Further high-quality studies on digital health are required. Trial RegistrationPROSPERO CRD42022327305; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=327305

Introduction: This study evaluated the cost-effectiveness of nivolumab plus ipilimumab (NI) versus pemetrexed plus cisplatin/carboplatin (C) as the first-line treatment for unresectable malignant pleural mesothelioma (MPM) from the perspective of US payers. Methods: A 10-year partitioned survival model was constructed using survival and safety data from the CheckMate 743 clinical trial. The output metrics of the model included the patient’s lifetime quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratio (ICER). Only direct medical costs were considered. One-way and probabilistic sensitivity analyses were conducted to assess the robustness of the results. Results: Among all randomized patients, group NI had an ICER of $475,677/QALY relative to group C. Among patients with epithelioid histology, group NI had an ICER of $760,955/QALY. Among patients with non-epithelioid histology, group NI had an ICER of $418,348/QALY. The ICERs of all three populations exceeded the willingness-to-pay threshold ($150,000). The results of one-way sensitivity analysis revealed that the cost of nivolumab had a great influence on the results. The results of probabilistic sensitivity analysis demonstrated that the possibility of NI being more economical in all randomized patients and in patients with non-epidemiology histology was 0. In patients with epithelioid histology, the probability that NI had an economic advantage was 0.6%. Conclusions: From the perspective of US payers, in patients with unresectable MPM, NI has no economic advantage over C.

Objective: Busulfan (BU) is a bi-functional DNA-alkylating agent used in patients undergoing hematopoietic stem cell transplantation (HSCT). Over the last decades, several population pharmacokinetic (pop PK) models of BU have been established, but external evaluation has not been performed for almost all models. The purpose of the study was to evaluate the predictive performance of published pop PK models of intravenous BU in adults using an independent dataset from Chinese HSCT patients, and to identify the best model to guide personalized dosing.Methods: The external evaluation methods included prediction-based diagnostics, simulation-based diagnostics, and Bayesian forecasting. In prediction-based diagnostics, the relative prediction error (PE%) was calculated by comparing the population predicted concentration (PRED) with the observations. Simulation-based diagnostics included the prediction- and variability-corrected visual predictive check (pvcVPC) and the normalized prediction distribution error (NPDE). Bayesian forecasting was executed by giving prior one to four observations. The factors influencing the model predictability, including the impact of structural models, were assessed.Results: A total of 440 concentrations (110 patients) were obtained for analysis. Based on prediction-based diagnostics and Bayesian forecasting, preferable predictive performance was observed in the model developed by Huang et al. The median PE% was -1.44% which was closest to 0, and the maximum F20 of 57.27% and F30 of 72.73% were achieved. Bayesian forecasting demonstrated that prior concentrations remarkably improved the prediction precision and accuracy of all models, even with only one prior concentration.Conclusion: This is the first study to comprehensively evaluate published pop PK models of BU. The model built by Huang et al. had satisfactory predictive performance, which can be used to guide individualized dosage adjustment of BU in Chinese patients.

Abstract Background Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. Gelsemium elegans Benth (GEB) is a traditional Chinese medicine commonly used for treatment for gastrointestinal cancer, including CRC. However, the underlying active ingredients and mechanism remain unknown. This study aims to explore the active components and the functional mechanisms of GEB in treating CRC by network pharmacology-based approaches. Methods Candidate compounds of GEB were collected from the Traditional Chinese Medicine@Taiwan, Traditional Chinese Medicines Integrated Database, Bioinformatics Analysis Tool for Molecular mechanism of Traditional Chinese Medicine, and published literature. Potentially active targets of compounds in GEB were retrieved from SwissTargetPrediction databases. Keywords “colorectal cancer”, “rectal cancer” and “colon cancer” were used as keywords to search for related targets of CRC from the GeneCards database, then the overlapped targets of compounds and CRC were further intersected with CRC related genes from the TCGA database. The Cytoscape was applied to construct a graph of visualized compound-target and pathway networks. Protein-protein interaction networks were constructed by using STRING database. The DAVID tool was applied to carry out Gene Ontology and Kyoto Encyclopedia of Genes and Genome pathway enrichment analysis of final targets. Molecular docking was employed to validate the interaction between compounds and targets. AutoDockTools was used to construct docking grid box for each target. Docking and molecular dynamics simulation were performed by Autodock Vina and Gromacs software, respectively. Results Fifty-three bioactive compounds were successfully identified, corresponding to 136 targets that were screened out for the treatment of CRC. Functional enrichment analysis suggested that GEB exerted its pharmacological effects against CRC via modulating multiple pathways, such as pathways in cancer, cell cycle, and colorectal cancer. Molecular docking analysis showed that the representative compounds had good affinity with the key targets. Molecular dynamics simulation indicated that the best hit molecules formed a stable protein-ligand complex. Conclusion This network pharmacology study revealed the multiple ingredients, targets, and pathways synergistically involved in the anti-CRC effect of GEB, which will enhance our understanding of the potential molecular mechanism of GEB in treatment for CRC and lay a foundation for further experimental research.

Background: Sunitinib has a narrow therapeutic window, with considerable differences between patients. Dosing based on pharmacokinetics (PK) may help overcome some of those issues. This study aims to evaluate and compare the cost-effectiveness of PK-guided individualized treatment of sunitinib with its standard dose in patients with metastatic renal cell carcinoma (mRCC). Methods: A comprehensive literature search was performed, and relevant values were used to provide information for the decision analysis model. Utility data were derived from published studies, and costs were obtained from the perspective of payers in China and the United States. A Markov model was established to evaluate the associated costs and health outcomes for patients. The primary outputs of the model included lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). One-way and probability sensitivity analyses were conducted to evaluate the potential uncertainties of parameters. Results: Cost-effective analysis showed that the QALY of the PK-guided group increased by 0.83 compared with that in the standard dose group. From the perspective of both countries’ health systems, the cost of PK-guided dose was lower than that of standard dose. Hence, PK-guided treatment was the dominant strategy. One-way and probability sensitivity analyses confirmed the reliability of these results. Conclusion: On the basis of currently available data, PK-guided sunitinib treatment may be a safe, effective, and economical intervention for patients with mRCC.

Gelsemium elegans (Gardner and Champ.) Benth. (Gelsemiaceae) (GEB) is a toxic plant indigenous to Southeast Asia especially China, and has long been used as Chinese folk medicine for the treatment of various types of pain, including neuropathic pain (NPP). Nevertheless, limited data are available on the understanding of the interactions between ingredients-targets-pathways. The present study integrated network pharmacology and experimental evidence to decipher molecular mechanisms of GEB against NPP. The candidate ingredients of GEB were collected from the published literature and online databases. Potentially active targets of GEB were predicted using the SwissTargetPrediction database. NPP-associated targets were retrieved from GeneCards, Therapeutic Target database, and DrugBank. Then the protein-protein interaction network was constructed. The DAVID database was applied to Gene Ontology and Kyoto Encyclopedia of Genes and Genome pathway enrichment analysis. Molecular docking was employed to validate the interaction between ingredients and targets. Subsequently, a 50 ns molecular dynamics simulation was performed to analyze the conformational stability of the protein-ligand complex. Furthermore, the potential anti-NPP mechanisms of GEB were evaluated in the rat chronic constriction injury model. A total of 47 alkaloids and 52 core targets were successfully identified for GEB in the treatment of NPP. Functional enrichment analysis showed that GEB was mainly involved in phosphorylation reactions and nitric oxide synthesis processes. It also participated in 73 pathways in the pathogenesis of NPP, including the neuroactive ligand-receptor interaction signaling pathway, calcium signaling pathway, and MAPK signaling pathway. Interestingly, 11-Hydroxyrankinidin well matched the active pockets of crucial targets, such as EGFR, JAK1, and AKT1. The 11-hydroxyrankinidin-EGFR complex was stable throughout the entire molecular dynamics simulation. Besides, the expression of EGFR and JAK1 could be regulated by koumine to achieve the anti-NPP action. These findings revealed the complex network relationship of GEB in the “multi-ingredient, multi-target, multi-pathway” mode, and explained the synergistic regulatory effect of each complex ingredient of GEB based on the holistic view of traditional Chinese medicine. The present study would provide a scientific approach and strategy for further studies of GEB in the treatment of NPP in the future.

Background: This study aimed to analyze the cost effectiveness of camrelizumab in the second-line treatment of advanced or metastatic esophageal squamous cell carcinoma in China.Methods: On the basis of the ESCORT clinical trial, a partitioned survival model was constructed to simulate the patient’s lifetime quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratio (ICER). One-way sensitivity and probability sensitivity analyses were performed to test the stability of the model.Results: Treatment of esophageal squamous cell carcinoma with camrelizumab added 0.36 QALYs and resulted in an incremental cost of $1,439.64 compared with chemotherapy, which had an ICER of $3,999 per QALY gained. The ICER was far lower than the threshold of willingness to pay for one time the GDP per capita in China. Sensitivity analysis revealed that the ICERs were most sensitive to the cost of drugs, but the parameters did not have a major effect on the results of the model.Conclusion: Camrelizumab is likely to be a cost-effective option compared with chemotherapy for patients with advanced or metastatic esophageal squamous cell carcinoma. This informs patient selection and clinical path development.

Polymyxin B (PMB) is the final option for treating multidrug-resistant Gram-negative bacterial infections. The acceptable pharmacokinetic/pharmacodynamic target is an area under the concentration–time curve across 24 h at a steady state (AUCss,24h) of 50–100 mg·h/L. The limited sampling strategy (LSS) is useful for predicting AUC values. However, establishing an LSS is a time-consuming process requiring a relatively dense sampling of patients. Further, given the variability among different centers, the predictability of LSSs is frequently questioned when it is extrapolated to other clinical centers. Currently, limited data are available on a reliable PMB LSS for estimating AUCss,24h. This study assessed and validated the practicability of LSSs established in the literature based on data from our center to provide reliable and ready-made PMB LSSs for laboratories performing therapeutic drug monitoring (TDM) of PMB. The influence of infusion and sampling time errors on predictability was also explored to obtain the optimal time points for routine PMB TDM. Using multiple regression analysis, PMB LSSs were generated from a model group of 20 patients. A validation group (10 patients) was used to validate the established LSSs. PMB LSSs from two published studies were validated using a dataset of 30 patients from our center. A population pharmacokinetic model was established to simulate the individual plasma concentration profiles for each infusion and sampling time error regimen. Pharmacokinetic data obtained from the 30 patients were fitted to a two-compartment model. Infusion and sampling time errors observed in real-world clinical practice could considerably affect the predictability of PMB LSSs. Moreover, we identified specific LSSs to be superior in predicting PMB AUCss,24h based on different infusion times. We also discovered that sampling time error should be controlled within −10 to 15 min to obtain better predictability. The present study provides validated PMB LSSs that can more accurately predict PMB AUCss,24h in routine clinical practice, facilitating PMB TDM in other laboratories and pharmacokinetics/pharmacodynamics-based clinical studies in the future.

Background: The PARP inhibitor olaparib has been shown to have clinical efficacy in patients with a germline BRCA mutation and ovarian or breast cancer. However, the high treatment cost associated with this drug limits its viability as a clinical treatment option. This work aims to evaluate the cost-effectiveness of olaparib as a maintenance treatment for metastatic pancreatic cancer from the perspective of the United States and China healthcare systems and provides valuable suggestions for clinical decision making.Method: A three-state Markov model (progression-free, progressed disease, death) was constructed using TreeAge Pro 2020 software to evaluate the economic value of olaparib vs. placebo maintenance treatment for metastatic pancreatic cancer based on the clinical data derived from phase III randomized controlled trial (POLO, ClinicalTrials.gov number, NCT02184195). Total costs, quality-adjusted life years and incremental cost-effectiveness ratio were used as economic indicators for this analysis. A 5-years horizon and 5%/year discount rates were used. One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) were performed to assess the model uncertainty.Results: The incremental cost-effectiveness ratios (ICERs) of the use of olaparib vs. placebo in China and the United States were $6,694/QALY and $13327/QALY, respectively. All ICERs were far below the thresholds of $30829 in China and $50000 in the United States. Sensitivity analysis confirmed a stable economic advantage in the use of olaparib vs. placebo as maintenance therapy in China and the United States.Conclusion: Olaparib was estimated to be more cost effective than placebo for the maintenance therapy of patients with a germline BRCA mutation and pancreatic cancer in China and the United States at thresholds of $30829 and $50000 per QALY, respectively.

Aim: We evaluated whether acute drug-induced liver injury (DILI) caused by adjuvant chemotherapy with epirubicin plus cyclophosphamide for early breast cancer was associated with estradiol (E2), luteinizing hormone (LH), and follicle-stimulating hormone (FSH).Methods: Reproductive hormone test results of breast cancer patients were collected in the first chemotherapy cycle. E2, LH, and FSH levels were loge-transformed to normally distributed variables and were assessed using Student’s t-test to determine significant differences between the case and control groups. Hormone levels were classified according to the interquartile range and analyzed by logistic regression to determine their association with DILI caused by chemotherapy.Results: Among the 915 enrolled patients (DILI group: 204; control group: 711), menopausal status, along with serum E2, LH, and FSH levels, did not substantially differ between case and control groups. However, in the premenopause subgroup (n = 483), we found a significant difference in the E2 level between the case and control groups (p = 0.001). After adjusting for age and body mass index, premenopausal patients with 152–2,813 pg/mL E2 showed a lower risk of chemotherapy-induced DILI than patients with ≤20 pg/mL E2 (odds ratio: 0.394; 95% confidence interval: 0.207–0.748). The linear trend χ2 test revealed that E2 levels in premenopausal patients with breast cancer were inversely associated with the development of DILI.Conclusion: High serum E2 levels are associated with a reduced DILI risk in premenopausal patients with breast cancer undergoing epirubicin plus cyclophosphamide adjuvant chemotherapy.

BackgroundThe aim of the present study was to evaluate the cost-effectiveness of durvalumab plus platinum–etoposide versus platinum–etoposide as first-line treatments for small-cell lung cancer from the perspective of the US payer.MethodsThis study established a partition survival model for three health states, metastasis probability, and safety data based on the CASPIAN clinical trial. The health utility value was mainly derived from the published literature. Only direct medical costs were considered. Sensitivity analyses were conducted to assess the robustness of the incremental cost per quality-adjusted life year (QALY).ResultsDurvalumab plus platinum–etoposide increased QALY by 0.220 compared to that observed with platinum–etoposide only. The cost increased by $78,198.75 and the incremental cost per QALY increased by $355,448.86. One-way and probability sensitivity analyses indicated that the model parameters varied within a limited range and had no significant effect on the results.ConclusionsAlthough durvalumab plus platinum–etoposide can improve quality of life, it also substantially increases the cost of medical treatment. Under a willingness-to-pay threshold of $100,000, durvalumab does not have a cost-effective comparative advantage.

The revised consensus guidelines for optimizing vancomycin doses suggest that maintaining the area under the concentration-time curve to minimal inhibitory concentration ratio (AUC/MIC) of 400–600 mg·h/L is the target pharmacokinetic/pharmacodynamic (PK/PD) index for efficacy. AUC-guided dosing approach uses a first-order pharmacokinetics (PK) equation to estimate AUC using two samples obtained at steady state and one-compartment model, which can cause inaccurate AUC estimation and fail to achieve the effective PK/PD target early in therapy (days 1 and 2). To achieve an efficacy target from the third or fourth dose, two innovative approaches (Method 1 and Method 2) to estimate vancomycin AUC at steady state (AUCSS) using two-compartment model and three or four levels after the first dose are proposed. The feasibility of the proposed methods was evaluated and compared with another published dosing algorithm (Method 3), which uses two samples and a one-compartment approach. Monte Carlo simulation was performed using a well-established population PK model, and concentration-time profiles for virtual patients with various degrees of renal function were generated, with 1000 subjects per group. AUC extrapolated to infinity (AUC0–∞) after the first dose was estimated using the three methods, whereas reference AUC (AUCref) was calculated using the linear-trapezoidal method at steady state after repeated doses. The ratio of AUC0–∞: AUCref and % bias were selected as the indicators to evaluate the accuracy of three methods. Sensitivity analysis was performed to examine the influence of change in each sampling time on the estimated AUC0–∞ using the two proposed approaches. For simulated patients with various creatinine clearance, the mean of AUC0–∞: AUCref obtained from Method 1, Method 2 and Method 3 ranged between 0.98 to 1, 0.96 to 0.99, and 0.44 to 0.69, respectively. The mean bias observed with the three methods was −0.10% to −2.09%, −1.30% to −3.59% and −30.75% to −55.53%, respectively. The largest mean bias observed by changing sampling time while using Method 1 and Method 2 were −4.30% and −10.50%, respectively. Three user-friendly and easy-to-use excel calculators were built based on the two proposed methods. The results showed that our approaches ensured sufficient accuracy and achieved target PK/PD index early and were superior to the published methodologies. Our methodology has the potential to be used for vancomycin dose optimization and can be easily implemented in clinical practice.

Abstract Background This study aims to establish a new indicator based on the anatomical therapeutic chemical/defined daily dose (ATC/DDD) system. Methods Utilization data of antibiotics of inpatients in a university hospital were used to calculate the indicators of use rate (UR), use density (UD), and ratio of use density to use rate (UD/UR). According to the professional characteristics, the recommended values of UD/UR in different departments were established respectively. Crosswise comparison and appropriateness evaluation between different treatment groups with the same profession were performed. For individual inpatients with abnormally increased drug utilization index (DUI) and ratios of antimicrobial course to length of stay (C/S), detailed analysis was performed to examine whether any irrational drug utilization occurred. Results The indicator UD/UR combines both dose and duration of treatment, which were the two main factors affecting the appropriateness of clinical application of antibiotics. Thus, it can more sensitively reveal the drug utilization of inpatients receiving antibiotics. UD/UR is also more suitable for evaluating the clinical appropriateness of antibiotic application than the macroscopic indicator, total UD, and could be applied at the macroscopic and microscopic levels. Conclusions The ratio UD/UR has great practical value and can serve as a reference for evaluating the appropriateness of clinical application of antibiotics.

Gelsemium elegans Benth (GEB), also known as heartbreak grass, is a highly poisonous plant belonging to the family Loganiaceae and genus Gelsemium that has broad application prospects in medicine. This article reviews its chemical components, pharmacological effects, toxicity mechanisms, and research progress in clinical applications in recent years. Indole alkaloids are the main active components of GEB and have a variety of pharmacological and biological functions. They have anti-tumor, anti-inflammatory, analgesic, and immunomodulation properties, with the therapeutic dose being close to the toxic dose. Application of small-dose indole alkaloids fails to work effectively, while high-dose usage is prone to poisoning, aggravating the patient’s conditions. Special caution is needed, especially to observe the changes in the disease condition of the patients in clinical practice. In-depth research on the chemical components and mechanisms of GEB is essential to the development of promising lead compounds and lays the foundation for extensive clinical application and safe usage of GEB in the future.

Abstract Background Automated systems (MicroScan WalkAway 96 Plus, Phoenix 100, and Vitek 2 Compact) are widely used in clinical laboratories nowadays. The aim of this study is to evaluate the performance of these three systems for susceptibility testing of aminoglycosides and fluoroquinolones against Carbapenem-resistant Enterobacteriaceae (CRE). Methods A total of 75 CRE isolates were used in this study. Quinolone resistance determinants (QRDs) (qnrA, qnrB, qnrC, qnrD, qnrS, aac(6′)-Ib-cr, oqxAB and qepA) and aminoglycoside resistance determinants (ARDs) (aac(6′)-Ib, armA, npmA, rmtA, rmtB, rmtC, rmtD and rmtE) of these CRE were screened by PCR. The MICs of aminoglycosides (gentamicin and amikacin) and fluoroquinolones (ciprofloxacin and levofloxacin) to CRE obtained with the automated systems were compared with the reference method (agar dilution method). Results Totally, 97.3% (73/75) of CRE harbored QRDs. The qnr gene was the most common QRD determinant identified in 68 (96.7%), followed by aac (6′)-Ib-cr in 56 (74.7%), oqxAB in 23 (30.7%), and qepA in 2 (2.7%), respectively. 22.7% (17/75) of CRE harbored ARD determinants. rmtA, rmtB and npmA were identified among these isolates in 6 (8.0%), 6 (8.0%) and 5 (6.7%), respectively. A total of 900 results were obtained in this study. Overall, the total error rate was 9.89%. Twenty-eight very major errors (3.11%), 22 major errors (2.44%) and 39 minor errors (4.33%) were identified against agar dilution method. The very major errors were almost evenly distributed between results for fluoroquinolones (2.89%) and aminoglycosides (3.33%), while the major errors and minor errors were more commonly found in the results of fluoroquinolones (3.11% and 6.44%, respectively) than aminoglycosides (1.78% and 2.22%, respectively). Conclusions Our study shows that testing difficulties in susceptibility testing do exist in automated systems. We suggest clinical laboratories using automated systems should consider using a second, independent antimicrobial susceptibility testing method to validate aminoglycosides and fluoroquinolones susceptibility.

Aim: Doxorubicin (DOX) is an effective chemotherapeutic drug. However, its clinical application may be hampered by dose-dependent cardiotoxicity. Alcohol metabolite and doxorubicinol (DOXol) were the most prominent components in DOX-induced cardiotoxicity. It is necessary to elucidate the level of DOXol in heart in vivo and whether DOXol could cause toxicity at such a concentration.Methods: The pharmacokinetics and heart distribution of DOX and its second metabolite DOXol were determined in rats. Based on this concentration level in vivo, H9C2 cell was used to examine the cardiotoxicity of DOX and DOXol. Real-time cell viability was determined using the xCelligence system and the membrane-permeable of DOX, and DOXol was also assessed by determining the intracellular and extracellular concentrations.Results: Our data showed that DOX level was higher than DOXol level in heart tissue. DOX had a high level in intracellular H9C2 cell and was the primary cytotoxic agent. DOXol had a significantly low level in heart tissue and less cytotoxicity than that of DOX in H9C2. DOXol in heart could not diffuse from plasma but only form in the heart. DOXol could not enter cell as easy as DOX. The less cardiotoxicity of DOXol might be caused by the less intracellular concentration.