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

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.