Comparing the performance and coverage of selected in silico (liver) metabolism tools relative to reported studies in the literature to inform analogue selection in read-across: A case study.

Changes in the regulatory landscape of chemical safety assessment call for the use of New Approach Methodologies (NAMs) including read-across to fill data gaps. One critical aspect of analogue evaluation is the extent to which target and source analogues are metabolically similar. In this study, a set of 37 structurally diverse chemicals were compiled from the EPA ToxCast inventory to compare and contrast a selection of metabolism in silico tools, in terms of their coverage and performance relative to metabolism information reported in the literature. The aim was to build understanding of the scope and capabilities of these tools and how they could be utilised in a read-across assessment. The tools were Systematic Generation of Metabolites (SyGMa), Meteor Nexus, BioTransformer, Tissue Metabolism Simulator (TIMES), OECD Toolbox, and Chemical Transformation Simulator (CTS). Performance was characterised by sensitivity and precision determined by comparing predictions against literature reported metabolites (from 44 publications). A coverage score was derived to provide a relative quantitative comparison between the tools. Meteor, TIMES, Toolbox, and CTS predictions were run in batch mode, using default settings. SyGMa and BioTransformer were run with user-defined settings, (two passes of phase I and one pass of phase II). Hierarchical clustering revealed high similarity between TIMES and Toolbox. SyGMa had the highest coverage, matching an average of 38.63% of predictions generated by the other tools though was prone to significant overprediction. It generated 5,125 metabolites, which represented 54.67% of all predictions. Precision and sensitivity values ranged from 1.1-29% and 14.7-28.3% respectively. The Toolbox had the highest performance overall. A case study was presented for 3,4-Toluenediamine (3,4-TDA), assessed for the derivation of screening-level Provisional Peer Reviewed Toxicity Values (PPRTVs), was used to demonstrate the practical role in silico metabolism information can play in analogue evaluation as part of a read-across approach.

The cost-effectiveness of as-needed budesonide/formoterol versus low-dose inhaled corticosteroid maintenance therapy in patients with mild asthma in the UK.

BACKGROUND: As-needed budesonide/formoterol is effective in patients with mild asthma for whom low-dose inhaled corticosteroid (ICS) maintenance therapy is appropriate. We assessed the cost-effectiveness of this regimen versus maintenance low-dose ICS plus as-needed short-acting ß2-agonist (SABA). METHODS: A probabilistic Markov cohort model was developed that simulated time within/outside severe asthma exacerbations, conducted from a UK NHS perspective with a 70-year time horizon. Clinical efficacy inputs were derived from the SYGMA 2 trial. Patients with mild asthma eligible for low-dose maintenance ICS therapy received as-needed budesonide/formoterol 200/6 µg or twice-daily budesonide 200 µg maintenance therapy plus as-needed terbutaline 0.5 mg. A severe exacerbation was defined as worsening asthma requiring systemic corticosteroid use alone/in combination with an emergency department visit, or hospitalisation for acute asthma. Utility values were derived from SYGMA 2 EQ-5D-5L data, and all-cause- and asthma-related mortality, reduction in utility of an exacerbation, and costs were based on published data. The base-case analysis discount rate was 3.5%. Model robustness was evaluated with one-way sensitivity, probabilistic sensitivity, and two scenario analyses. RESULTS: On average, as-needed budesonide/formoterol was associated with a £292.99 cost saving and quality-adjusted life year (QALY) gains of 0.001 versus ICS + SABA. At a willingness-to-pay of £20,000/QALY, as-needed budesonide/formoterol had >85% probability of being cost-effective versus ICS + SABA. Key drivers were budesonide/formoterol and budesonide maintenance annual exacerbation rates, mean daily budesonide/formoterol inhalations, and costs and outcomes discount rates. CONCLUSIONS: From a UK healthcare payer perspective, as-needed budesonide/formoterol is a cost-effective option for the treatment of mild asthma versus regular ICS.

The SYGMA programme of phase 3 trials to evaluate the efficacy and safety of budesonide/formoterol given 'as needed' in mild asthma: study protocols for two randomised controlled trials.

BACKGROUND: In many patients with mild asthma, the low frequency of symptoms and the episodic nature of exacerbations make adherence to regular maintenance treatment difficult. This often leads to over-reliance on short-acting ß2-agonist (SABA) reliever medication and under-treatment of the underlying inflammation, with poor control of asthma symptoms and increased risk of exacerbations. The use of budesonide/formoterol 'as needed' in response to symptoms may represent an alternative treatment option for patients with mild asthma. METHODS/DESIGN: The SYmbicort Given as needed in Mild Asthma (SYGMA) programme consists of two 52-week, double-blind, randomised, multicentre, parallel-group, phase 3 trials of patients aged 12 years and older with a clinical diagnosis of asthma for at least 6 months, who would qualify for treatment with regular inhaled corticosteroids (ICS). SYGMA1 aims to recruit 3750 patients who will be randomised to placebo twice daily (bid) plus as-needed budesonide/formoterol 160/4.5 µg, placebo bid plus as-needed terbutaline 0.4 mg, or budesonide 200 µg bid plus as-needed terbutaline 0.4 mg. The primary objective is to demonstrate the superiority of as-needed budesonide/formoterol over as-needed terbutaline for asthma control, as measured by well-controlled asthma weeks; a secondary objective is to establish the noninferiority of as-needed budesonide/formoterol versus maintenance budesonide plus as-needed terbutaline using the same outcome measure. SYGMA2 aims to recruit 4114 patients who will be randomised to placebo bid plus as-needed budesonide/formoterol 160/4.5 µg, or budesonide 200 µg bid plus as-needed terbutaline 0.4 mg. The primary objective is to demonstrate the noninferiority of as-needed budesonide/formoterol over budesonide bid plus as-needed terbutaline as measured by the annualised severe exacerbation rate. In both studies, use of all blinded study inhalers will be recorded electronically using Turbuhaler® Usage Monitors. DISCUSSION: Given the known risks of mild asthma, and known poor adherence with regular inhaled corticosteroids, the results of the SYGMA programme will help to determine the efficacy and safety of as-needed budesonide/formoterol therapy in mild asthma. Patient recruitment is complete, and completion of the phase 3 studies is planned in 2017. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02149199 SYGMA1 and NCT02224157 SYGMA2. Registered on 16 May 2014 and 19 August 2014, respectively.