The salmeterol anomaly and the need for a urine threshold

Abstract

Salmeterol is a long acting beta2-agonist (LABA) widely used for treatment of airways disease.There is evidence that beta2-agonists, including salmeterol, have the potential for performance enhancing effects when delivered at supratherapeutic doses. For this reason, all beta2-agonists are currently on the Prohibited List issued by the World Anti-Doping Agency (WADA) regardless of dosing route with some exemptions for inhaled salbutamol, formoterol, and salmeterol when used at therapeutic inhaled doses. For 2020, salmeterol use is permitted up to a therapeutic dosing threshold of 200 µg daily, but unlike salbutamol and formoterol, there is an anomaly; currently there is no urine threshold to control for supratherapeutic dosing beyond this dosing threshold. Salmeterol, however, is reportable as an Adverse Analytical Finding (AAF) at levels above 10 ng/ml. Complicating matters is that following inhalation, salmeterol parent drug is present at relatively low levels compared to other beta2-agonists due to rapid metabolism to the metabolite, alpha-hydroxysalmeterol, which is typically present at higher levels than parent drug. Moreover, peak parent drug levels following permitted therapeutic dosing are below the minimum required performance level (MRPL) of 10 ng/ml for salmeterol (50% of the MRPL that analytical laboratories are required to meet for non-threshold beta2agonists), hence the presence of salmeterol may be unreported. For consistency, a urine threshold should be introduced for salmeterol as matter of priority, to balance the needs of athletes that use salmeterol therapeutically up to the agreed dosing threshold, with the need to control supratherapeutic dosing for doping intentions and athlete harm minimisation.

Pharmacokinetics of salmeterol and its main metabolite α‐hydroxysalmeterol after acute and chronic dry powder inhalation in exercising endurance‐trained men: Implications for doping control

“…To strengthen the analysis, we also included data on urine concentrations of salmeterol and α‐hydroxysalmeterol from 37 biobank urine samples collected 1½–6 h after inhalation of 200 μg salmeterol in 13 endurance athletes (six with asthma and in current treatment with inhaled glucocorticoid, aged 23 ± 3 years and weighing 72 ± 8 kg), as well as 27 urine samples collected 4 h after inhalation of 100 μg salmeterol in 20 recreationally active men (10 with asthma, aged 25 ± 4 years and weighing 75 ± 6 kg) 22 . The salmeterol and α‐hydroxysalmeterol concentrations from the latter study were multiplied by 2 to approximate the maximum dosing limit of 200 μg, assuming dose linearity as observed during the pharmacokinetic trial (Figures 4 and 5) and apparent from between‐study analysis 41 . Thus, our prognostic analysis is based on 183 urine samples collected up to 6 h following inhalation of salmeterol in 44 individuals from three studies during controlled experimental conditions.…”

“…As recently highlighted by Jacobson and Hostrup, 41 the current salmeterol regulations are associated with some challenges that are potentially exploitable by athletes. The inclusion of α-hydroxysalmeterol in routine doping testing would provide superior prognostic accuracy to detect supratherapeutic use.…”

“…In summary, our data show that a combined salmeterol and α‐hydroxysalmeterol threshold may be suitable for discriminating between therapeutic and supratherapeutic inhalation of salmeterol. As recently highlighted by Jacobson and Hostrup, 41 the current salmeterol regulations are associated with some challenges that are potentially exploitable by athletes. The inclusion of α‐hydroxysalmeterol in routine doping testing would provide superior prognostic accuracy to detect supratherapeutic use.…”

“…22 The salmeterol and α-hydroxysalmeterol concentrations from the latter study were multiplied by 2 to approximate the maximum dosing limit of 200 μg, assuming dose linearity as observed during the pharmacokinetic trial (Figures 4 and 5) and apparent from between-study analysis. 41 Thus, our prognostic analysis is based on 183 urine samples collected up to 6 h following inhalation of salmeterol in 44 individuals from three studies during controlled experimental conditions.…”

Annual banned‐substance review: Analytical approaches in human sports drug testing 2019/2020

“…These regulations include maximum permitted doses for formoterol, salbutamol, and salmeterol, 10 with corresponding urinary thresholds existing for formoterol and salbutamol, 133 while salmeterol is reported as AAF when exceeding 50% of the MRPL (i.e., 10 ng/ml). This strategy was called into question by Jacobson and Hostrup in the light of literature data regarding urinary levels of salmeterol following controlled therapeutic and supratherapeutic administrations as well as the aforementioned performance‐enhancing properties of the drug, and the authors suggest the installment of a threshold also for this β 2 ‐agonist 134 . More recently, tretoquinol was included as an example of banned β 2 ‐agonists in the Prohibited List, and Okano et al reported on the implementation of the drug and its main metabolites (tretoquinol glucuronide; tretoquinol sulfate; and free, glucurono‐, and sulfo‐conjugated O ‐methyl tretoquinol) into a routine ITP 135 .…”