Evaluation of urine thresholds for an expanded range of beta2-agonists

Code: 20C13GJ

Objective: To determine urine thresholds consistent with maximum therapeutic dose of: salmeterol.

Study A: Salmeterol
A salmeterol threshold study will be conducted using a similar protocol to that previously used by our team, consisting of two acute urine PK trials 25 over one week; one under normal conditions at baseline, followed by salmeterol dosing for one week and then a second acute PK trial performed under stressful conditions with heat and dehydration22. During the acute phase, we will also assess the effect of salmeterol on muscle strength, peak power and time trial performance utilising a placebo-controlled crossover design. After the second PK trial, subjects are randomly allocated 5 weeks of treatment with placebo or salmeterol (1:1) to assess the effect of salmeterol on muscle mass, fat mass, muscle strength, time trial performance and peak power during cycling measured at six weeks (completion).

Subjects: Thirty six healthy trained men and women (equal male:female) will be recruited for the study, non-smokers, no history of chronic disease, and recreationally active (>5 h/wk). 

Clinical Study Procedure: Pre-intervention will consist of general health screen, lung function test, and VO2 max will be determined by incremental bike ergometer to exhaustion using standard laboratory protocols. A baseline Wingate test protocol will be administered to participants during this period.5 Pharmacokinetic (PK) intervention in all subjects (n=36) will consist of salmeterol delivered by pMDI (200 µg dose) at time 0, followed by urine collection at 0.5, 1, 2, 4, 8 and 24 hours under resting conditions. Salmeterol will be continued to be delivered daily (100 µg twice daily – home administration with supervision monitored by Skype/Facetime) with spot urine collection until the 7th day at which point a 200 µg dose will be administered and a second acute phase PK study will be conducted under identical time (urine collection at 0.5, 1, 2, 4, 8 and 24 hours). The second acute PK study, however, will encompass stressful conditions, namely accumulation of dose (as noted previously using a similar protocol for terbutaline 25) but also with exercise (time trial) under heat (30-35°C) as per our previous work with terbutaline22. Subjects will then be randomised to salmeterol:placebo 1:1 and continue treatment for a further 5 weeks (6 weeks total duration) and undertake a second Wingate test to assess effects of the intervention on exercise performance using our previously applied protocols 5 – further spot urine sampling will not occur during this time. Subjects will be asked to avoid any CYP3A4 inhibitors such as grapefruit juice during the chronic phase. 

Analytical: Urine samples will be analysed by racemic assay (a simple modification based on our previous racemic work 26). We will investigate the alpha-hydroxysalmeterol metabolite and salmeterol in urine, with a total of around 612 samples for the acute and the intermediate chronic spot sampling phase treatment arm.