# Pharmacometric‐Based Evaluation of Salmeterol and Its Metabolite α‐Hydroxysalmeterol in Plasma and Urine: Practical Implications for Doping Control

## TL;DR

This study evaluates how well current doping rules detect the asthma drug salmeterol, suggesting changes to improve accuracy.

## Contribution

A population pharmacokinetic model is developed to assess the effectiveness of current doping thresholds for salmeterol.

## Key findings

- Athletes have significantly higher salmeterol urine concentrations compared to other subjects.
- Current minimum reporting levels may miss therapeutic doses of salmeterol in urine.
- Adjusting the minimum reporting level or analytical targets could improve doping detection.

## Abstract

Salmeterol is a commonly used β2‐agonist included on the List of Prohibited Substances and Methods published by the World Anti‐Doping Agency (WADA). We developed a population pharmacokinetic (popPK) model to describe the PK of salmeterol including its major metabolite, α‐hydroxysalmeterol, in plasma and urine after inhalation. The model was used to evaluate the ability of the current minimum reporting level (MRL) of 10 ng/mL for salmeterol to discriminate between permitted and prohibited use of salmeterol. Six studies on healthy participants, chronic asthmatics, or athletes were pooled and provided a total of 1175 concentrations (275 and 398 for salmeterol and 185 and 317 for α‐hydroxysalmeterol in plasma and urine, respectively) from 92 individuals. A two‐compartment model assuming intravenous‐like bolus absorption best depicted plasma salmeterol PK, with a complete parent conversion into α‐hydroxysalmeterol. Because urine volumes were only recorded in two studies, a separate urine compartment was defined to approximate physiologic micturition. Athletes had a 63% higher salmeterol plasma clearance and a 191% greater salmeterol urinary rate constant compared to other subjects, resulting in significantly higher salmeterol urine concentrations. Our popPK model suggests that salmeterol concentrations in urine at therapeutic doses (100 μg twice daily) are unlikely to be reported using the current MRL. However, to improve its sensitivity to detect cases of doping, an adjustment in the MRL and/or a different analytical target would be recommended.

What is the current knowledge on the topic?
○Salmeterol is a commonly used β2‐agonist included on the List of Prohibited Substances and Methods of the World Anti‐Doping Agency (WADA) with a specified dosing limit of 200 μg in any 24 h period via inhaled administration. A minimum reporting level of 10 ng/mL is currently used to flag urine doping samples as an indication of doping.
What question did this study address?
○Our model‐based meta‐analysis was performed to provide the basis for evaluating the ability of the current WADA approach to discriminate between the permitted and prohibited use of salmeterol.
What does this study add to our knowledge?
○This study provides a comprehensive description of the pharmacokinetics of salmeterol and its major metabolite in plasma and urine and discusses the impact of different dosing regimens on the urine concentrations of salmeterol in athletes/endurance‐trained individuals.
How might this change drug discovery, development, and/or therapeutics?
○The model‐based simulations suggest that the current approach for evaluating suspected salmeterol misuses could be improved by revising the dosing regulations, refining the analytical methodology, and/or adjusting the MRL.

What is the current knowledge on the topic?
○Salmeterol is a commonly used β2‐agonist included on the List of Prohibited Substances and Methods of the World Anti‐Doping Agency (WADA) with a specified dosing limit of 200 μg in any 24 h period via inhaled administration. A minimum reporting level of 10 ng/mL is currently used to flag urine doping samples as an indication of doping.

Salmeterol is a commonly used β2‐agonist included on the List of Prohibited Substances and Methods of the World Anti‐Doping Agency (WADA) with a specified dosing limit of 200 μg in any 24 h period via inhaled administration. A minimum reporting level of 10 ng/mL is currently used to flag urine doping samples as an indication of doping.

What question did this study address?
○Our model‐based meta‐analysis was performed to provide the basis for evaluating the ability of the current WADA approach to discriminate between the permitted and prohibited use of salmeterol.

Our model‐based meta‐analysis was performed to provide the basis for evaluating the ability of the current WADA approach to discriminate between the permitted and prohibited use of salmeterol.

What does this study add to our knowledge?
○This study provides a comprehensive description of the pharmacokinetics of salmeterol and its major metabolite in plasma and urine and discusses the impact of different dosing regimens on the urine concentrations of salmeterol in athletes/endurance‐trained individuals.

This study provides a comprehensive description of the pharmacokinetics of salmeterol and its major metabolite in plasma and urine and discusses the impact of different dosing regimens on the urine concentrations of salmeterol in athletes/endurance‐trained individuals.

How might this change drug discovery, development, and/or therapeutics?
○The model‐based simulations suggest that the current approach for evaluating suspected salmeterol misuses could be improved by revising the dosing regulations, refining the analytical methodology, and/or adjusting the MRL.

The model‐based simulations suggest that the current approach for evaluating suspected salmeterol misuses could be improved by revising the dosing regulations, refining the analytical methodology, and/or adjusting the MRL.