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8 The salbutamol passport: how to rule out an adverse analytical finding from serial urine tests
  1. Daren Austin1,
  2. Morten Hostrup2,
  3. Sheila M Bird3
  1. 1Senior Fellow and Senior Director, Clinical Pharmacology, GlaxoSmithKline
  2. 2Associate Professor, Section of Integrative Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen
  3. 3MRC Biostatistics Unit, University of Cambridge Institute for Public Health

Abstract

Salbutamol is used widely by elite athletes in treatment of asthma and related conditions, such as exercise-induced bronchoconstriction. In competitive sport, salbutamol is permitted by inhalation at doses up to 1600 µg/day, not to exceed 800 µg in any 12 hour period. WADA has established a urinary salbutamol Decision Limit for a presumed adverse analytical finding (AAF) of 1200 ng/mL. Urine salbutamol levels greater than this are deemed to be a result of prohibited use or excessive supratherapeutic inhalation. Studies have shown that under dehydrated conditions, exercise increases the risk of exceeding the Decision Limit after single inhaled doses of 1600 µg. One means of explaining an AAF is a Pharmacokinetic (PK) Study to establish whether an athlete is an outlier with higher urine concentrations than typical. However, a recent salbutamol case from the 2017 Vuelta a España, deemed it impractical and impossible to conduct a valid PK study capable of recreating the complex conditions of an athlete competing in such an event. Another means of explanation is the ‘Salbutamol Passport’. This is a statistical model derived from serial test data obtained from an event during periods of stable salbutamol use. After adjustment for dose and dosing frequency, the Salbutamol Passport can be used to predict an expected concentration range for days when an athlete might increase their salbutamol intake due to worsening symptoms. Since the number of tests during stable use is typically small, the method uses propagation of uncertainty in mean and variance of the log-transformed salbutamol concentrations to derive expected bands for any dose and frequency of interest. The method is demonstrated with data from a cyclist competing in the 2007 Giro d’Italia. The athlete provided four salbutamol tests whilst taking 400 ug/day with geometric mean 461 ng/mL (95% CL: 352–604) and one test of 1352 ng/mL after allegedly increasing his dose to 700 ug/day. Extrapolating the 400 ug/day data to 700 ug/day, and assuming an increase from twice-daily to three-times daily dosing, the Salbutamol Passport prediction is 1050 ng/mL (95%PI: 802–1375). Since the observed test falls within the 95% prediction interval, the result would not constitute an AAF. This conclusion is unchanged after adjustment of salbutamol levels to a urine specific gravity of 1.020.

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