Perrine Courlet (1), Irene Mazzoni (2), Olivier Rabin (2), Jérôme Biollaz (1), Thierry Buclin (1), Monia Guidi (1,3)
(1) Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. (2) Research & Prohibited List, World Anti-Doping Agency, Montreal, Canada. (3) Centre for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Objectives: Salbutamol was included in the List of Prohibited Substances and Methods of the World Anti-Doping Agency (WADA) in 2004 (1). While oral salbutamol is banned, inhaled salbutamol is permitted but with a dosage restriction to a maximum of 800 µg twice daily. The WADA established a Decision Limit (DL, 1200 ng/mL) based on urine concentration to distinguish between prohibited use and therapeutic inhalation (2). This study aimed at evaluating the ability of the WADA DL to differentiate permitted inhalation from forbidden oral intake or supratherapeutic inhaled doses.
Methods: Studies were identified based on a literature search using Pubmed and projects supported by the WADA. Salbutamol concentration-time profile in plasma and its excretion in urine was characterized through a model-based meta-analysis (MBMA) of individual and aggregate data using NONMEM 7.4 (ADVAN13). Data were collected after inhalation or oral administration of a large range of doses under a variety of conditions. The population pharmacokinetic (PK) analysis was first performed using plasma concentrations, and subsequently adding urine data after fixing the absorption parameters. Two separate compartments for the lung and the gut were modeled to characterize absorption after inhalation (inhaled and swallowed dose fractions) while using only the swallowed route after oral administration (3). The fraction of dose transferred into the lungs was fixed to 20% (4). Since urine volumes were not available, the addition of a urine compartment with a constant urine formation rate allowed describing the urine volume production. Studies reported measurements either corrected for urine specific gravity (USG) or not. Statistical accommodations for the MBMA were made once a satisfactory description of all data was achieved. In addition, random effects were all weighted by (Nobs = number of individuals contributing to aggregate plasma or urine PK profiles), to increase confidence in studies conducted in larger populations. The influence of physical exercise on salbutamol PK was quantified. Finally, model-based simulations of several dosage regimens were performed.
Results: We elaborated a model adequately fitting the plasma and urine concentration-time profiles of the 13 studies included in our MBMA. Overall, the analysis included 121 plasma concentrations (43 individual data and 78 mean profiles) and 796 urine concentrations (747 individual data and 49 mean profiles). Salbutamol PK profile was adequately described by a one-compartment model with absorption described as above. Various pharmaco-statistical refinements were tested. In the final model, typical value of salbutamol clearance was 28 L·h-1 (inter-individual variability IIV, CV%: 39%), distribution volume 205 L (no IIV) and urine production 0.0467 L·h-1 (38% and 74% for USG corrected and uncorrected values, respectively). Residual errors were estimated separately for individual and aggregate data. Physical exercise showed a significant impact on PK profile (urine production decreased by 15% compared to individuals at rest). Simulations revealed that essentially none of the individuals inhaling 200 µg four times a day (a relatively high dosage for therapeutic use), 600 µg twice daily or 400 µg twice daily would reach urine concentrations above the WADA DL. Urine PK profiles after inhalation of 800 µg twice daily (maximal permitted dosage) or oral administration of 2 mg once daily overlap largely, with approximately 1% of subjects exceeding the DL. Finally, salbutamol administered orally at 8 mg once daily (a dosage considered to increase peak power in athletes (5)) led to 63% of subjects overcoming the DL.
Conclusions: The reliance on modern MBMA approaches enabled taking into account the largest possible base of available evidence to validate the discriminative power of the WADA DL. While violation of the World Anti-Doping Code regulation can be strongly suspected in individuals showing very high salbutamol urine concentrations, uncertainty remains for values close to the DL, compatible with both permitted therapeutic drug use and violation. The current WADA rules could be improved by a reasonable limitation of inhaled dosages allowed in therapeutic exemption to 600 µg twice daily. The use of such a model can also help WADA experts in their evaluation of suspected doping cases through confronting the athlete’s allegations about treatment intake with their urinary concentrations.
References:
[1] The world anti-doping code. International standard. Prohibited list: World Anti-Doping Agency; 2020 [Available from: https://www.wada-ama.org/sites/default/files/wada_2020_english_prohibited_list_0.pdf.
[2] WADA statement on the salbutamol treshold/decision limit 2018 [Available from: https://www.wada-ama.org/sites/default/files/note_15may.pdf.
[3] Auclair B, Wainer IW, Fried K, Koch P, Jerussi TP, Ducharme MP. A population analysis of nebulized (R)-albuterol in dogs using a novel mixed gut-lung absorption PK-PD model. Pharm Res. 2000;17(10):1228-35.
[4] Chrystyn H. Methods to identify drug deposition in the lungs following inhalation. British journal of clinical pharmacology. 2001;51(4):289-99.
[5] Hostrup M, Kalsen A, Auchenberg M, Bangsbo J, Backer V. Effects of acute and 2-week administration of oral salbutamol on exercise performance and muscle strength in athletes. Scand J Med Sci Sports. 2016;26(1):8-16.
Reference: PAGE 29 (2021) Abstr 9627 [www.page-meeting.org/?abstract=9627]
Poster: Drug/Disease Modelling - Other Topics