Comparison Between Sotorasib with Docetaxel for the Treatment of Chinese Patients with Previously Treated NSCLC with KRASG12C Mutation: A Cost-Effectiveness Analysis to Inform Drug Pricing.

INTRODUCTION: This study sought to investigate the affordable price of sotorasib among patients with previously treated advanced KRASG12C-mutant non-small cell lung cancer (NSCLC) through a cost-effectiveness analysis from the perspectives of both the Chinese healthcare system and the patients. METHODS: We developed a Markov model spanning a 20-year time horizon with a cycle length of 21 days. Our data were derived from the CodeBreaK 200 clinical trial, supplemented with published literature, publicly available national databases, and local hospitals. The primary outcomes were the affordable prices of sotorasib which would result in the incremental cost-effectiveness ratios (ICERs) of sotorasib relative to docetaxel below the preset willing-to-pay (WTP) threshold. Sensitivity analyses were performed to evaluate the model's robustness. RESULTS: At the national level, from the perspective of the Chinese healthcare system and patients, the price of sotorasib should be lower than US$0.04673 and $0.03231, respectively, to make it affordable, which is equivalent to $1346 and $931 per box (120 mg × 240 pieces). At the provincial level, the price ceiling of sotorasib/mg fluctuated between $0.04084 to $0.08061 from the Chinese healthcare system's perspective and between $0.02642 to $0.06620 from the patients' perspective. Probabilistic sensitivity analyses revealed that, as the price of sotorasib decreased, its likelihood of being cost-effective increased. CONCLUSION: Sotorasib might be a cost-effective therapy in China. The pharmaco-economic evidence generated from this study has significant implications not only for guiding the drug pricing of the upcoming sotorasib but also for determining the reimbursement ratio for its potential inclusion in the National Reimbursement Drugs List in the future.

Identification of the human Cytochrome P450 enzymes (P450s) responsible for metabolizing infigratinib to its pharmacologically active Metabolites, BHS697, and CQM157, and assessment of their in vitro inhibition of P450s and UDP-glucuronosyltransferases (UGTs).

Infigratinib, an oral FGFR inhibitor for advanced cholangiocarcinoma, yielded two active metabolites, BHS697 and CQM157, with similar receptor affinity. Our study characterized P450s that are responsible for the metabolism of infigratinib to its two major active metabolites, BHS697 and CQM157. In vitro inhibition of P450s and UGTs by infigratinib, BHS697 or CQM157 was further investigated. The unbound apparent Km values for metabolism of infigratinib to BHS697 by HLM, human recombinant CYP2C8, CYP2C19, CYP2D6 and CYP3A4 enzymes are 4.47, 0.65, 2.50, 30.6 and 2.08 µM, while Vmax values are 90.0 pmol/min/mg protein, 0.13, 0.027, 0.81, and 0.56 pmol/min/pmol protein, respectively. The unbound apparent Km value for metabolism of infigratinib to CQM157 by HLM is 0.049 µM, while the Vmax value is 0.32 pmol/min/mg protein respectively. In HLM, infigratinib displayed moderate inhibition of CYP3A4 and CYP2C19 and weak or negligible inhibition of other P450 isoforms. BHS697 exhibited weak inhibition of CYP2B6, CYP2C9, CYP2C19 and CYP3A4, and no inhibition of CYP2C8 and CYP2D6. CQM157 moderately inhibited CYP2C9 and CYP3A4, and weakly or negligibly inhibited other P450 isoforms. Regarding UGTs, infigratinib moderately inhibited UGT1A4 and weakly inhibited UGT1A1, respectively. BHS697 weakly inhibited UGT1A1. In contrast, CQM157 moderately inhibited both UGT1A1 and UGT1A4. Our findings provide novel insights into the metabolism of and potential DDIs implicating infigratinib.

Cost-Effectiveness of Ibrutinib for Chronic Lymphocytic Leukemia Treatment in India: Is Evidence Really at Crossroads?

In recent years, newer drugs, such as ibrutinib, have shown promising improvements in the survival of patients with chronic lymphocytic leukemia (CLL). Despite their effectiveness, concerns about their cost have arisen, prompting the need for an evaluation of their cost-effectiveness. However, recent assessments of ibrutinib's cost-effectiveness for treating CLL in India reveal divergent conclusions. The discord centers on divergent cost-effectiveness thresholds, comparator regimens, cost calculations, and outcome valuation approaches. Such discrepancies affect public health decisions and patient care. The recommendation calls for adherence to methodological guidelines by future studies, fostering consistent findings to empower policy makers and clinicians in leveraging economic evidence for informed decision making in CLL treatment strategies.

Cost-utility analysis of add-on vericiguat for the treatment of chronic heart failure with reduced ejection fraction in China.

OBJECTIVE: This study aimed to evaluate the cost-utility of the addition of vericiguat for treating chronic heart failure (CHF) in China from the healthcare payer's perspective. METHODS: A Markov model was built to estimate the cost and utility of treating CHF using vericiguat plus standard treatment (vericiguat group) vs. standard treatment alone (standard treatment group). The clinical parameters (mortality of cardiovascular and hospitalization rate of HF) were calculated according to the VICTORIA clinical trial. The HF cost and utility data were obtained from the literature published in China. One-way sensitivity analysis and probability sensitivity analysis were performed. RESULTS: According to the 13-year model, vericiguat was more expensive (155599.07 CNY vs. 259396.83 CNY) and more effective (4.41 QALYs vs. 4.54 QALYs). The incremental cost-utility ratio (ICUR) was 802389.27 CNY per QALY. One-way sensitivity analysis revealed that cardiovascular mortality in the two groups was the parameter that had the greatest impact on the results. The GDP per capita in 2022 in China was 85,700 CNY. The probability sensitivity analysis (PSA) showed that the probability of vericiguat being cost-effective was only 41.7% at the willingness-to-pay (WTP) threshold of 3 times GDP per capita (257,100 CNY). CONCLUSIONS: In China, the treatment of CHF with vericiguat is not cost-effective. The drug price could decrease to 145.8 CNY, which could be considered cost-effective.

Adherence and Persistence Among Risdiplam-Treated Individuals with Spinal Muscular Atrophy: A Retrospective Claims Analysis.

INTRODUCTION: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletions and/or mutations in the survival of motor neuron 1 (SMN1) gene. Risdiplam, the first and only oral SMN2 pre-mRNA splicing modifier, is US Food and Drug Administration-approved for the treatment of pediatric and adult patients with SMA. For patients with SMA, long-term adherence to and persistence with an SMA treatment may be important for achieving maximum clinical benefits. However, real-world evidence on patient adherence to and persistence with risdiplam is limited. METHODS: This retrospective study examined real-world adherence and persistence with risdiplam from a specialty pharmacy in patients with SMA over a 12-month period. Adherence was estimated by using proportion of days covered (PDC) and was calculated over variable (time between first and last fill) and fixed (time from first fill to study period end) intervals. Persistence was defined as no gap in supply ≥ 90 days. Patients were included if the time between the index date and study observation period was ≥ 12 months, if they initiated risdiplam between August 2020 and September 2022, received ≥ 2 risdiplam fills, and had an SMA diagnosis associated with a risdiplam fill. Subgroup analyses of risdiplam adherence and persistence were performed by age and primary payer type. RESULTS: The proportion of patients (N = 1636) adherent at 12 months based on variable and fixed interval PDC was 93% and 79%, respectively. Adherence was high among patients on commercial insurance, Medicaid, or Medicare (range 86-96%). Mean persistence was 330.4 days. The highest proportion of patients who were persistent were on Medicaid (81%). CONCLUSION: These findings demonstrate that patient adherence to and persistence with risdiplam treatment were high, including across all subgroups tested.

Clinical assessment of momelotinib drug-drug interactions via CYP3A metabolism and transporters.

Momelotinib-approved for treatment of myelofibrosis in adults with anemia-and its major active metabolite, M21, were assessed as drug-drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple-dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single-dose rifampin), and a strong CYP3A4 inducer (multiple-dose rifampin). Momelotinib DDI perpetrator potential (multiple-dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively). DDI was assessed from changes in maximum plasma concentration (Cmax), area under the concentration-time curve (AUC), time to reach Cmax, and half-life. The increase in momelotinib (23% Cmax, 14% AUC) or M21 (30% Cmax, 24% AUC) exposure with ritonavir coadministration was not clinically relevant. A moderate increase in momelotinib (40% Cmax, 57% AUC) and minimal change in M21 was observed with single-dose rifampin. A moderate decrease in momelotinib (29% Cmax, 46% AUC) and increase in M21 (31% Cmax, 15% AUC) were observed with multiple-dose rifampin compared with single-dose rifampin. Due to potentially counteracting effects of OATP1B1/1B3 inhibition and CYP3A4 induction, multiple-dose rifampin did not significantly change momelotinib pharmacokinetics compared with momelotinib alone (Cmax no change, 15% AUC decrease). Momelotinib did not alter the pharmacokinetics of midazolam (8% Cmax, 16% AUC decreases) or 1'-hydroxymidazolam (14% Cmax, 16% AUC decreases) but increased rosuvastatin Cmax by 220% and AUC by 170%. Safety findings were mild in this short-term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments.

Cost-Effectiveness of Technologies for the Treatment of Spinal Muscular Atrophy: A Systematic Review of Economic Studies.

OBJECTIVES: This study aims to systematically collect data on cost-effectiveness analyses that assess technologies to treat type I and II spinal muscular atrophy and evaluate their recommendations. METHODS: A structured electronic search was conducted in 4 databases. Additionally, a complementary manual search was conducted. Complete economic studies that evaluated nusinersen, risdiplam, onasemnogene abeparvovec (OA), and the best support therapy (BST) from the health system's perspective were selected. The incremental cost-effectiveness ratios were compared with various thresholds for the analysis. The review was registered a priori in PROSPERO (CRD42022365391). RESULTS: Twenty studies were included in the analyses. They were all published between 2017 and 2022 and represent the recommendations in 8 countries. Most studies adopted 5, 6, or 10-state Markov models. Some authors took part in multiple studies. Four technologies were evaluated: BST (N = 14), nusinersen (N = 19), risdiplam (N = 5), and OA (N = 9). OA, risdiplam, and nusinersen were considered inefficient compared with the BST. Risdiplam and OA were generally regarded as cost-effective when compared with nusinersen. Because nusinersen is not a cost-effective drug, no recommendation can be derived from this result. Risdiplam and OA were compared in 2 studies that presented opposite results. CONCLUSIONS: Nusinersen, risdiplam, and OA are being adopted worldwide as a treatment for spinal muscular atrophy. Despite that, the pharmacoeconomic analyses show that the technologies are not cost-effective compared with the BST. The lack of controlled studies for risdiplam and OA hamper any conclusions about their face-to-face comparison.

Cost-effectiveness analysis of abrocitinib compared with standard of care in adult moderate-to-severe atopic dermatitis in Japan.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a significant clinical, economic, and human burden. The JAK1 Atopic Dermatitis Efficacy and Safety (JADE) program's Phase 3 trials demonstrated that as a treatment for moderate-to-severe AD in adults with previous exposure to immunotherapy, abrocitinib showed superior efficacy and safety compared with standard of care (SoC), consisting of topical corticosteroids. This study assessed the cost-effectiveness of abrocitinib with SoC versus SoC alone for this patient population in Japan from a societal perspective. A hybrid decision tree and Markov model were used to capture the initial treatment and long-term maintenance phases. Clinical inputs at 16 weeks were obtained through a Bayesian network meta-analysis of four pivotal trials from the JADE program. Clinical inputs at 52 weeks were derived from the JADE EXTEND trial. Response-specific utility inputs were obtained from published literature. Resource use, costs, and productivity inputs were gathered from Japanese claims analysis, literature, public documents, and expert opinion. Costs and quality-adjusted life years (QALYs) were discounted at 2.0% per year and incremental cost-effectiveness ratios (ICERs) were calculated. Sensitivity and scenario analyses were performed to validate the base case results and explore a payer perspective. Over a lifetime horizon and with the base-case societal perspective, abrocitinib produced a mean gain of 0.75 QALYs, incremental costs of JPY (¥) 2 270 386 (USD [$] 17 265.6), and a resulting ICER of ¥3 034 514 ($23 076.5) per QALY compared with SoC. From a payer perspective, the incremental costs increased to ¥4 476 777 ($34 044.4), with an ICER of ¥5 983 495 ($45 502.6) per QALY. The results were most sensitive to treatment-specific, response-based utility weights, drug costs, and productivity-related inputs. From a Japanese societal perspective, abrocitinib demonstrated superior QALYs and with a willingness-to-pay threshold of ¥5 000 000 ($38 023.4) per QALY, can be considered cost-effective compared with SoC as a treatment for moderate-to-severe AD in adult patients with previous immunosuppressant exposure.

Cost-Utility Analysis of Vericiguat in Heart Failure with Reduced Ejection Fraction After Worsening Heart Failure Events in China.

OBJECTIVE: Vericiguat is a new medication to demonstrate clinical efficacy in heart failure with reduced ejection fraction (HFrEF) after worsening heart failure (WHF) events, but its cost-utility was unknown. We aimed to assess the cost-utility of combining the application of vericiguat with standard treatment in HFrEF patients who had WHF events. METHODS: A multistate Markov model was implemented to mimic the economic results of HFrEF patients who had WHF events in China after receiving vericiguat or placebo. An analysis of cost-utility was conducted; most parameters were set according to the published studies and related databases. All the utilities and costs were decreased at a rate of 5% annually. The incremental cost-effectiveness ratios (ICERs) were the primary outcome measure. We also conducted sensitivity analyses. RESULTS: Over a 20 year lifetime horizon, additional use of vericiguat led to an elevated cost from US$9725.03 to US$20,660.76 at the current vericiguat costs. This was related to increased quality-adjusted life years (QALYs) from 2.50 to 2.66, along with an ICER of US$65,057.24 per QALY, which was over the willingness-to-pay (WTP) threshold of US$36,096.30 per QALY. If the vericiguat costs were discounted at 80%, it contributed to an ICER of US$12,226.77 per QALY. Additional use of vericiguat for patients with plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) of ≤ 5314 pg per ml produced an ICER of US$23,688.46 per QALY. The outcomes of the one-way sensitivity analysis showed the risk of death from cardiovascular disease in both groups was variable with the highest sensitivity. The probabilistic sensitivity analysis showed that 41.6% of the mimicked population receiving vericiguat combined with standard therapy was cost-effective at the WTP threshold of US$36,096.30 per QALY. CONCLUSIONS: From the perspective of Chinese public healthcare system, the combined use of vericiguat and standard treatment in patients with HFrEF following WHF events did not generate advantages in cost-utility in China but was a cost-effective therapeutic strategy for those who with plasma NT-proBNP of ≤ 5314 pg per ml.

Structure-Guided Discovery and Preclinical Assessment of Novel (Thiophen-3-yl)aminopyrimidine Derivatives as Potent ERK1/2 Inhibitors.

The RAS-RAF-MEK-ERK signaling cascade is abnormally activated in various tumors, playing a crucial role in mediating tumor progression. As the key component at the terminal stage of this cascade, ERK1/2 emerges as a potential antitumor target and offers a promising therapeutic strategy for tumors harboring BRAF or RAS mutations. Here, we identified 36c with a (thiophen-3-yl)aminopyrimidine scaffold as a potent ERK1/2 inhibitor through structure-guided optimization for hit 18. In preclinical studies, 36c showed powerful ERK1/2 inhibitory activities (ERK1/2 IC50 = 0.11/0.08 nM) and potent antitumor efficacy both in vitro and in vivo against triple-negative breast cancer and colorectal cancer models harboring BRAF and RAS mutations. 36c could directly inhibit ERK1/2, significantly block the phosphorylation expression of their downstream substrates p90RSK and c-Myc, and induce cell apoptosis and incomplete autophagy-related cell death. Taken together, this work provides a promising ERK1/2 lead compound for multiple tumor-treatment drug discovery.

Predicting the in vivo developmental toxicity of fenarimol from in vitro toxicity data using PBTK modelling-facilitated reverse dosimetry approach.

In vitro methods are widely used in modern toxicological testing; however, the data cannot be directly employed for risk assessment. In vivo toxicity of chemicals can be predicted from in vitro data using physiologically based toxicokinetic (PBTK) modelling-facilitated reverse dosimetry (PBTK-RD). In this study, a minimal-PBTK model was constructed to predict the in-vivo kinetic profile of fenarimol (FNL) in rats and humans. The model was verified by comparing the observed and predicted pharmacokinetics of FNL for rats (calibrator) and further applied to humans. Using the PBTK-RD approach, the reported in vitro developmental toxicity data for FNL was translated to in vivo dose-response data to predict the assay equivalent oral dose in rats and humans. The predicted assay equivalent rat oral dose (36.46 mg/kg) was comparable to the literature reported in vivo BMD10 value (22.8 mg/kg). The model was also employed to derive the chemical-specific adjustment factor (CSAF) for interspecies toxicokinetics variability of FNL. Further, Monte Carlo simulations were performed to predict the population variability in the plasma concentration of FNL and to derive CSAF for intersubject human kinetic differences. The comparison of CSAF values for interspecies and intersubject toxicokinetic variability with their respective default values revealed that the applied uncertainty factors were adequately protective.

Comparative Effectiveness of Tofacitinib and Adalimumab in Axial Spondyloarthritis: A Real-World Clinical Context Multicenter Study.

INTRODUCTION: Tofacitinib, an oral Janus kinase inhibitor, is a putative choice in the treatment of axial spondyloarthritis (AxSpA). The objective of this study was to compare the effectiveness and tolerability of tofacitinib with adalimumab, in AxSpA, in a real-world clinical setting. METHODS: In this multicentric medical records review study, adult patients with active AxSpA treated with either tofacitinib 5 mg twice daily or adalimumab 40 mg subcutaneously fortnightly were recruited. Effectiveness was measured with Ankylosing Spondylitis Disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Drug-cost analysis was calculated with Incremental Cost-Effectiveness Ratio (ICER drug ). RESULTS: Among the 266 patients, 135 were treated with tofacitinib and 131 with adalimumab (follow-up: 6.5 ± 1.6 months). Mean improvement of BASDAI (3.39 ± 0.09 vs. 3.14 ± 1.16, respectively) and that of ASDAS (1.78 ± 0.68 vs. 2.07 ± 2.08, respectively) were comparable between the adalimumab and tofacitinib groups. A higher proportion of patients achieved BASDAI50 response in the second (49.5% vs. 31.6%) and fourth month (83.9% vs. 62.8%) and ASDAS low disease activity in the fourth month (71.6% vs. 47.9%) in the adalimumab group. All disease activity measurements were similar by the sixth month in both groups. A higher proportion of patients in the tofacitinib group than in the adalimumab group required change in therapy (14.8% vs. 7.6%, respectively). ICER drug for adalimumab compared with tofacitinib was US $188.8 per patient in the adalimumab group for each person-month with BASDAI <4. CONCLUSIONS: Tofacitinib showed comparable effectiveness with adalimumab in patients with AxSpA at the sixth month, despite lesser response in the initial months, with favorable ICER drug .

Osimertinib in Patients With Treatment-Naive EGFR-Mutant Non-small Cell Lung Cancer: Overall Survival, Post-progression Management and Budget Impact Analysis in Real-World.

INTRODUCTION: The observational multicenter prospective FLOWER study (NCT04965701) confirmed effectiveness and safety of osimertinib in the real-world (RW) management of untreated EGFR-mutant advanced non-small cell lung cancer (aNSCLC) patients. METHODS: Herein, we report updated survival data, post-progression management, cost/effectiveness and budget impact (BI) of osimertinib compared with a RW population receiving gefitinib or erlotinib. RESULTS: Overall, 189 Caucasian patients receiving first-line osimertinib were included. After a follow-up of 20.7 months, 74(39.2%) patients discontinued osimertinib, median time-to-treatment discontinuation (mTTD) was 27.9 months, overall survival 36.8 months. At progression, tissue biopsy was performed in 29 (56.9%), liquid biopsy in 15 (29.4%) and both in 7 (13.7%) cases. The most frequent resistant mechanism was MET amplification (N = 14, 29.8%). At data cutoff, 13 (6.9%) patients were continuing osimertinib beyond progression; 52 (67.5%) received second-line treatment; no further treatments were administered in 25 (32.5%) cases. Thirty-three (63.4%) patients received chemotherapy, 12(23.1%) TKIs combination. Cost-effectiveness analysis showed a total cost per patient based on RW mTTD of 98,957.34€, 21,726.28€ and 19,637.83€ for osimertinib, erlotinib and gefitinib, respectively. The incremental cost-effectiveness ratio (ICER)/month for osimertinib was 359,806.0€/life-year-gained (LYG) and 197,789.77€/LYG compared to erlotinib and gefitinib. For osimertinib, the BI-gap between RW-TTD and theoretical-TTD was 16,501.0€ per patient. CONCLUSIONS: This updated analysis confirms the effectiveness of osimertinib in RW. Although the ICER of osimertinib seems not cost-effective, additional costs for the management of disease progression to old generation TKIs were not considered in this study. The BI-gap suggests RW mTTD as a more reliable measure for expense estimation.

Cost-effectiveness of first-line versus second-line use of brigatinib followed by lorlatinib in patients with ALK-positive non-small cell lung cancer.

Background: The ALTA-1 L trial and EXP-3B arm of NCT01970865 trial found that both brigatinib and lorlatinib showed durable and robust responses in treating ALK-positive non-small cell lung cancer (NSCLC) patients. However, brigatinib and lorlatinib treatments are costly and need indefinite administration until the disease progression. Thus, it remains uncertain whether using brigatinib followed by lorlatinib before chemotherapy is cost-effective compared to reserving these two drugs until progression after chemotherapy. Methods: We used a Markov model to assess clinical outcomes and healthcare costs of treating ALK-positive NSCLC individuals with brigatinib followed by lorlatinib before chemotherapy versus a strategy of reserving these drugs until progression after chemotherapy. Transition probabilities were estimated using parametric survival modeling based on multiple clinical trials. The drug acquisition costs, adverse events costs, administration costs were extracted from published studies before and publicly available data. We calculated lifetime direct healthcare costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios from the perspective of a United States payer. Results: Our base-case analysis indicated that the incremental cost-effectiveness ratios of using first-line brigatinib followed by lorlatinib compared with second-line brigatinib followed by lorlatinib is $-400,722.09/QALY which meant that second-line brigatinib followed by lorlatinib had less costs and better outcomes. Univariate sensitivity analysis indicated the results were most sensitive to the cost of brigatinib. Probability sensitivity analysis revealed that using brigatinib followed by lorlatinib before chemotherapy had a 0% probability of cost-effectiveness versus delaying these two drugs until progression after chemotherapy at a willingness-to-pay threshold of $150,000 per QALY. Sensitivity analyses conducted revealed the robustness of this result, as incremental cost-effectiveness ratios never exceeded the willingness-to-pay threshold. Conclusion: Using brigatinib as first-line treatment followed by lorlatinib for ALK-positive NSCLC may not be cost-effective given current pricing from the perspective of a United States payer. Delaying brigatinib followed by lorlatinib until subsequent lines of treatment may be a reasonable strategy that could limit healthcare costs without affecting clinical outcomes. More mature data are needed to better estimate cost-effectiveness in this setting.

Pesticides in surface water of the Ondas river watershed, western Bahia, Brazil: Spatial-seasonal distribution and risk assessment.

This study investigated the occurrence and seasonal distribution of different classes of pesticides in surface waters of the Ondas River Watershed, as well as potential risks to the aquatic health and human water consumption in the western region of Bahia state, Brazil. Two gas chromatography-mass spectrometry analytical methods were applied to monitor 34 pesticides in water samples collected during both the dry and rainy seasons at 17 sites. Upon individual analysis, only γ-HCH, methoxychlor, demeton-S, methyl parathion, fenitrothion, chlorpyrifos, and azoxystrobin exhibited statistically significant differences between seasons. During rainy season, concentration medians of residues were higher for γ-HCH (74.7 ng L-1), methoxychlor (25.1 ng L-1), and azoxystrobin (47.2 ng L-1), potentially linked to historical contamination or illegal use. Conversely, pesticides like methyl parathion, fenitrothion, and chlorpyrifos, belonging to the organophosphate class, showed higher concentration medians in the dry period, measuring 75.1, 5.50, and 10.8 ng L-1, respectively, probably due to region crop activities. The risk quotient (RQ) assessment for aquatic life indicated that 59.0% of the samples in the dry season and 76.0% in the rainy season had RQ values greater than one, signifying a critical scenario for species conservation. Regarding human consumption, elevated risks were observed for heptachlor in both sampling periods and for azoxystrobin during the rainy season, surpassing RQ levels above 1, indicating danger in untreated water ingestion. Additionally, 24.0% and 53.0% of the samples in the dry and rainy seasons, respectively, contained at least one pesticide exceeding the EU resolution limit (100 ng L-1). Therefore, considering this information, implementing mitigation measures to avoid the river's contamination becomes imperative.

Cost-effectiveness comparison of dalpiciclib and abemaciclib combined with an aromatase inhibitor as first-line treatment for HR+/HER2- advanced breast cancer.

OBJECTIVES: CDK4/6 inhibitors dalpiciclib and abemaciclib have been approved by the Chinese National Medical Products Administration as first-line treatment for postmenopausal females with hormone receptor-positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (ABC). We aimed to assess the cost-effectiveness of dalpiciclib plus letrozole/anastrozole (non-steroidal aromatase inhibitor [NSAI]) compared with abemaciclib plus NSAI as a first-line treatment for HR+/HER2- ABC in China. METHODS: We constructed a Markov model with three health states to evaluate health and economic outcomes of first-line treatment with dalpiciclib plus NSAI and abemaciclib plus NSAI for HR+/HER2- ABC. Efficacy data was obtained from MONARCH3 and DAWNA-2 trials. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated. RESULTS: Compared with abemaciclib plus NSAI, dalpiciclib plus NSAI resulted in 4.27 additional QALYs, with an ICER of $14827.4/QALY. At a willingness-to-pay threshold of 3 times gross domestic product per capita in China for 2023 ($37721.5/QALY), the cost-effectiveness probability of dalpiciclib plus NSAI was 77.42%. CONCLUSIONS: From the perspective of Chinese payers, dalpiciclib plus NSAI appears to be a cost-effective strategy compared with abemaciclib plus NSAI for the first-line treatment of patients with HR+/HER2- ABC in China. CLINICAL TRIAL REGISTRATION: MONARCH3, www.clinicaltrials.gov, identifier is NCT02246621 and DAWNA-2, www.clinicaltrials.gov, identifier is NCT03966898.

Effect of vine leaves processing on Azoxystrobin, Fenazaquin and Indoxacarb residues dissipation: processing factors and consumer safety assessment.

The effect of vine leaves processing techniques on Azoxystrobin, Fenazaquin, and Indoxacarb residues was investigated. Residue extraction following field application of pesticides and leaf processing was carried out using the QuEChERS method, with analysis conducted by LC-MS/MS. In dry conservation, Azoxystrobin's half-life was estimated to exceed a year, Fenazaquin's was 18 days, and Indoxacarb's was 142 days. Azoxystrobin had a half-life of 261 days, Fenazaquin had a half-life of 9 days, and Indoxacarb's half-life exceeded a year in brine conservation. It is recommended to use dry conservation because it results in an average 60 % reduction in residue levels for the three pesticides. Boiling water significantly reduced pesticide residues (Azoxystrobin -40.3 %, Indoxacarb -22.4 %, and Fenazaquin -28.8 %). It is recommended to use boiling water for washing, as it shows an average removal rate of approximately 30 %. The health risk assessment indicated that consuming vine leaves posed no health risk for consumers, but overall exposure to residues must be considered.

Assessment of the Effects of Abrocitinib on the Pharmacokinetics of Probe Substrates of Cytochrome P450 1A2, 2B6 and 2C19 Enzymes and Hormonal Oral Contraceptives in Healthy Individuals.

BACKGROUND AND OBJECTIVE: Abrocitinib is an oral small-molecule Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis. In vitro studies indicated that abrocitinib is a weak time-dependent inhibitor of cytochrome P450 (CYP) 2C19/3A and a weak inducer of CYP1A2/2B6/2C19/3A. To assess the potential effect of abrocitinib on concomitant medications, drug-drug interaction (DDI) studies were conducted for abrocitinib with sensitive probe substrates of these CYP enzymes. The impact of abrocitinib on hormonal oral contraceptives (ethinyl estradiol and levonorgestrel), as substrates of CYP3A and important concomitant medications for female patients, was also evaluated. METHODS: Three Phase 1 DDI studies were performed to assess the impact of abrocitinib 200 mg once daily (QD) on the probe substrates of: (1) 1A2 (caffeine), 2B6 (efavirenz) and 2C19 (omeprazole) in a cocktail study; (2) 3A (midazolam); and (3) 3A (oral contraceptives). RESULTS: After multiple doses of abrocitinib 200 mg QD, there is a lack of effect on the pharmacokinetics of midazolam, efavirenz and contraceptives. Abrocitinib increased the area under the concentration time curve from 0 to infinity (AUCinf) and the maximum concentration (Cmax) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUCinf of caffeine by 40% with lack of effect on Cmax. CONCLUSIONS: Based on the study results, abrocitinib is a moderate inhibitor of CYP2C19. Caution should be exercised when using abrocitinib concomitantly with narrow therapeutic index medicines that are primarily metabolized by CYP2C19 enzyme. Abrocitinib is a mild inhibitor of CYP1A2; however, the impact is not clinically relevant, and no general dose adjustment is recommended for CYP1A2 substrates. Abrocitinib does not inhibit CYP3A or induce CYP1A2/2B6/2C19/3A and does not affect the pharmacokinetics of contraceptives. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov registration IDs: NCT03647670, NCT05067439, NCT03662516.

Abrocitinib, tralokinumab and upadacitinib for treating moderate-to-severe atopic dermatitis.

Background: Atopic dermatitis is a chronic relapsing inflammatory skin condition. One of the most common skin disorders in children, atopic dermatitis typically manifests before the age of 5 years, but it can develop at any age. Atopic dermatitis is characterised by dry, inflamed skin accompanied by intense itchiness (pruritus). Objectives: To appraise the clinical and cost effectiveness of abrocitinib, tralokinumab and upadacitinib within their marketing authorisations as alternative therapies for treating moderate-to-severe atopic dermatitis compared to systemic immunosuppressants (first-line ciclosporin A or second-line dupilumab and baricitinib). Data sources: Studies were identified from an existing systematic review (search date 2019) and update searches of electronic databases (MEDLINE, EMBASE, CENTRAL) to November 2021, from bibliographies of retrieved studies, clinical trial registers and evidence provided by the sponsoring companies of the treatments under review. Methods: A systematic review of the clinical effectiveness literature was carried out and a network meta-analysis undertaken for adults and adolescents at different steps of the treatment pathway. The primary outcome of interest was a combined response of Eczema Area and Severity Index 50 + Dermatology Life Quality Index ≥ 4; where this was consistently unavailable for a step in the pathway, an analysis of Eczema Area and Severity Index 75 was conducted. A de novo economic model was developed to assess cost effectiveness from the perspective of the National Health Service in England. The model structure was informed through systematic review of the economic literature and by consulting clinical experts. Effectiveness data were obtained from the network meta-analysis. Costs and utilities were obtained from the evidence provided by sponsoring companies and standard UK sources. Results: Network meta-analyses indicate that abrocitinib 200 mg and upadacitinib 30 mg may be more effective, and tralokinumab may be less effective than dupilumab and baricitinib as second-line systemic therapies. Abrocitinib 100 mg and upadacitinib 15 mg have a more similar effectiveness to dupilumab. Upadacitinib 30 and 15 mg are likely to be more effective than ciclosporin A as a first-line therapy. Upadacitinib 15 mg, abrocitinib 200 and 100 mg may be more effective than dupilumab in adolescents. The cost effectiveness of abrocitinib and upadacitinib for both doses is dependent on the subgroup of interest. Tralokinumab can be considered cost-effective as a second-line systemic therapy owing to greater cost savings per quality-adjusted life-year lost. Conclusions: The primary strength of the analysis of the three new drugs compared with current practice for each of the subpopulations is the consistent approach to the assessment of clinical and cost effectiveness. However, the conclusions are limited by the high uncertainty around the clinical effectiveness and lack of data for the primary outcome for comparisons with baricitinib and for the adolescent and adult first-line populations. Future work and limitations: The most significant limitation that Eczema Area and Severity Index 50 + Dermatology Life Quality Index ≥ 4 could not be obtained for the adolescent and adult first-line systemic treatment populations is due to a paucity of data for dupilumab and ciclosporin A. A comparison of the new drugs against one another in addition to current practice would be beneficial to provide a robust view on which treatments are the most cost-effective. Study registration: This study is registered as PROSPERO CRD42021266219. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: 135138) and is published in full in Health Technology Assessment; Vol. 28, No. 4. See the NIHR Funding and Awards website for further award information.

Atopic dermatitis is one of the most common skin conditions in children but can also develop in adulthood. People with atopic dermatitis have dry, red (inflamed) skin that is also extremely itchy (pruritus). There is no cure for atopic dermatitis. Therapy starts with topical treatments that are applied to the skin, such as emollients. Severe forms of atopic dermatitis are often treated with systemic treatments, which are drugs that are provided as tablets or an injection. Ciclosporin A is often the first systemic therapy given. If atopic dermatitis does not get better with ciclosporin A, options available in the National Health Service are dupilumab and baricitinib. New therapies that have been evaluated in clinical trials for atopic dermatitis but have not been assessed for use in the National Health Service are abrocitinib, tralokinumab and upadacitinib. The aim of this project is to review the medical benefits, risks and value for money for the National Health Service of abrocitinib, tralokinumab and upadacitinib for the treatment of moderate-to-severe atopic dermatitis in a multiple technology appraisal. Our review found that: For children aged between 12 and 18 years, abrocitinib and a low dose of upadacitinib (15 mg) are good value for money for the National Health Service. For adults who need a first systemic treatment, upadacitinib is unlikely to be good value for money for the National Health Service. For adults who are still suffering from their atopic dermatitis after having a systemic treatment and need a different drug, upadacitinib 15 mg and tralokinumab could be good value for money for the National Health Service if they are used on their own. For adults who are still suffering from their atopic dermatitis after having a systemic treatment and need a different drug, but need to take it with steroid cream, abrocitinib 100 mg, upadacitinib 15 mg and tralokinumab could all be good value for money for the National Health Service.