Model‐based meta‐analysis of salbutamol pharmacokinetics and practical implications for doping control

Abstract

Salbutamol was included in the prohibited list of the World Anti-Doping Agency (WADA) in 2004. Although systemic intake is banned, inhalation for asthma is permitted but with dosage restrictions. The WADA established a urinary concentration threshold to distinguish accordingly prohibited systemic self-administration from therapeutic prescription by inhalation. This study aimed at evaluating the ability of the WADA threshold to differentiate salbutamol therapeutic use from violation of antidoping rules. Concentration-time profile of salbutamol in plasma and its excretion in urine was characterized through a model-based meta-analysis of individual and aggregate data collected after administration of a large range of doses following different modes of administration and under a variety of conditions. The developed model adequately fitted salbutamol plasma and urine concentration-time profiles of the 13 selected studies. Model-based simulations confirmed that a wide range of salbutamol urine concentrations might be measured after drug intake. Although violation of the WADA Code can be strongly suspected in individuals showing very high salbutamol urine concentrations, uncertainty remains for values close to the WADA threshold as they can be compatible with both permitted therapeutic use and violation. Although not entirely discriminant, the current WADA rule is globally supported by our appraisal. It could be further improved by a slight and reasonable adjustment of inhaled daily dosages allowed for therapeutic use. Our model might help antidoping experts in the evaluation of suspected doping cases through confronting the athlete's urine measurements with their allegations about salbutamol treatment. StudyHighlights WHATISTHECURRENTKNOWLEDGEONTHETOPIC?Salbutamol is included in the list of prohibited substances and methods of the World Anti-Doping Agency (WADA) banning systemic intake and permitting inhalation but with dosage restrictions. WADA also established a urinary concentration threshold to distinguish therapeutic from prohibited use.

Ionic liquid wrapped Co3O4 embedded N doped porous carbon for the precise monitoring of salbutamol in urine samples for dope tests

“…Moreover, the impact of IL on the electrochemically active electrode surface of Co 3 O 4 was further confirmed through the Randles-Sevcik eqn (7). 56 ip = 2.69 Â 105 An 3/2 D 1/2 red C Â v 1/2 (7) where ''A'' is the electrochemically active surface area, ''n'' denotes the number of electrons engaged in the oxidation or reduction of [Fe(CN) 6 ] À3/À4 , ''C'' denotes the concentration of [Fe(CN) 6 ] À3/À4 (5 Â 10 À2 mol cm À3 ), ''Dred'' elucidates the diffusion coefficient (7.6 Â 10 À6 cm 2 s À1 ) and ''v'' reveals the scan rate (100 mV). The electrochemically active surface area of IL@NC-Co was calculated to be 0.02 cm 2 .…”

“…6 Although SAL is rapidly absorbed after oral or inhalation administration, nearly 60-90% of the taken dose is excreted via urine within 24 h, half of which is unconjugated SAL and the other half is the 4A-O-sulfate derivative. 7 Thus, such evidence forces researchers to determine SAL selectively and precisely in less than 24 h in the urine of an athlete to evaluate the doping level. 8 Several analytical methods, including spectrophotometry 9 capillary electrophoresis, 10 high-performance liquid chromatography (HPLC), 11 electro-generated chemiluminescence 12 and electrochemical methods, 13 have been successfully applied for the precise determination of SAL to date.…”

“…6 Although SAL is rapidly absorbed after oral or inhalation administration, nearly 60–90% of the taken dose is excreted via urine within 24 h, half of which is unconjugated SAL and the other half is the 4A-O-sulfate derivative. 7 Thus, such evidence forces researchers to determine SAL selectively and precisely in less than 24 h in the urine of an athlete to evaluate the doping level. 8…”

Annual banned‐substance review—Analytical approaches in human sports drug testing 2021/2022–

“…112 On the other hand, maintaining respiratory health while protecting the integrity of sport is of utmost importance, which is why selected β 2 -agonists are permitted when used within defined maximum allowed daily dose. Model-based metaanalyses concerning the pharmacokinetics of salbutamol corroborated the appropriateness of these limits, whereas adjustments regarding permissive dosages were discussed, 113 fueled also by a recent study indicating a potential performance-enhancing effect of inhaled salbutamol at allowed dosages (i.e., 800 μg via inhalation). 114 The situation has been further complicated by the fact that drugs such as salbutamol or formoterol, for which urinary threshold levels of 1000 ng/ml respectively 40 ng/ml exist, 115 are composed of two enantiomers.…”

Optimal dosing of gliclazide—A model‐based approach

“…First‐order elimination was assumed, with inter‐individual variability (IIV) and inter‐study variability (ISV) on all parameters, implemented as log‐normally distributed. For aggregate data, the random variables (i.e., η and ω) were weighted by the arm size, similar to Courlet et al 40 Investigated implementation of residual error included additive, proportional and a combination thereof. Parameters of disposition were shared between the IR and MR formulations, allowing absorption model structure and parameters to differ, including the estimation of relative bioavailability between the formulations.…”