Effect of hyperhydration on the pharmacokinetics and detection of orally administered budesonide in doping control analysis

Abstract

The aim of the present study was to investigate if hyperhydration could influence the excretion and subsequent detection of budesonide (BDS) and its main metabolites (6β‐hydroxy‐budesonide and 16α‐hydroxy‐prednisolone) during doping control analysis by leading to concentrations below the WADA reporting level (30 ng/mL). The influence of hyperhydration on the plasma and urinary pharmacokinetic (PK) profiles of BDS and metabolites was also examined. Seven healthy physically active non‐smoking Caucasian males participated in a 15‐day clinical study. BDS was administered orally at a single dose of 9 mg on Days 1, 7, and 13. Hyperhydration was applied in the morning on two consecutive days, that is, 0 and 24 hours after first fluid ingestion. Water and a commercial sports drink were used as hyperhydration agents (20 mL/kg body weight). Results showed no significant difference (P > 0.05, 95% CI) on plasma or urinary PK parameters under hyperhydration conditions for all the analytes. However, significant differences (P < 0.05, 95% CI) due to hyperhydration were observed on the urinary concentrations of BDS and metabolites. To compensate the dilution effect due to hyperhydration, different adjustment methods were applied based on specific gravity, urinary flow rate, and creatinine. All the applied methods were able to adjust the concentration values close to the baseline ones for each analyte; however, specific gravity was the optimum method in terms of effectiveness and practicability. Furthermore, no masking of the detection sensitivity of BDS or its metabolites was observed due to hyperhydration either in plasma or urine samples.

Annual banned‐substance review: Analytical approaches in human sports drug testing 2019/2020

“…Here, the modification of the currently enforced reporting level from 30 to 40 ng/ml was suggested, which would be applicable also in case of hyperhydration scenarios, which were shown to exert no effect on the pharmacokinetics of orally administered budesonide (9 mg). The observed reduced urinary concentrations (as potentially provoked by athletes to decrease urinary concentrations of a banned substance below the reporting level) were shown to be adequately compensated by specific gravity adjustments, if required 164 …”

A novel approach to improve detection of glucocorticoid doping in sport with new guidance for physicians prescribing for athletes

“…The initial results were corroborated and expanded on by numerous studies published thereafter which further evidenced the systemic distribution by measuring not only urinary but also plasma concentrations of the drugs. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] As a consequence, the status of local injections in the WADA Prohibited List needed to be re-evaluated. 5-7 13 19 20 The need for reliable and practical guidance for physicians treating athletes with GCs has also been recognised by WADA since the first inclusion of GCs on the Prohibited List.…”

“…However, different studies have shown the need to establish compound-specific RLs given the diversity of administration routes and doses, as well as pharmacokinetic and pharmacodynamic properties between the different GCs. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] The ideal RL should not produce AAFs after permitted administrations or negative results after prohibited use. When testing athletes, the potential for AAFs after permitted administrations for therapeutic purposes have to be precluded, therefore the RL must be based on concentrations obtained after permitted administrations.…”

“…All relevant studies are presented in table 2. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] For other GCs, with limited or no data available, the RL has been maintained at 30 ng/mL until further data are generated in the future.…”

Elimination profiles of betamethasone after different administration routes: Evaluation of the reporting level and washout periods to ensure safe therapeutic administrations

“…For this reason, a criterion to distinguish allowed and prohibited administration is needed in antidoping controls, in order to ensure safe treatments by allowed routes of administration and to detect the use of prohibited routes of administration during competitions. A general urinary reporting level of 30 ng/ml was established by WADA to perform the discrimination 12 ; however, different studies have shown that the use of a single criterion is not suitable for all GCs given the diversity of administration routes, doses and pharmacokinetic and pharmacodynamic properties of the compounds of the group 13–23 …”