I. Athanasiadou1,2, I. A. Kechagia1, C. Georgakopoulos2, A. Dokoumetzidis1, G. Valsami1
1Laboratory of Biopharmaceutics & Pharmacokinetics, Faculty of Pharmacy, National & Kapodistrian University of Athens, Panepistimiopolis-Zographou 15771, Athens, Greece, 2Anti Doping Lab Qatar, P.O. Box 27775, Doha, Qatar
Objectives: To study the effect of hyperhydration on the urine pharmacokinetic profile of the model drug budesonide (BDS) and its possible implication as a doping masking procedure used by athletes.
Methods: A one-compartment PopPK model was constructed from non-compartmental PK values taken from literature [1], using the methodology described in [2]. This model was implemented in MatLab SimBiology toolbox, and 1000 subjects administered a single per os dose of 9 mg BDS, were simulated. The renal regulation of urine volume [3] and the conditions of water retention [4] were taken into account for urine production modelling. The normal BDS PK urine profiles and additional PK profiles after 10, 20 and 30 ml of water consumption/kg of body weight, were generated, in order to simulate the effect of hyperhydration on urine PK profile of BDS for 3 hydration levels. Simulation of urine sampling collection schedule was also performed and used to evaluate the effect of hyperhydration on measured BDS urine concentration levels during doping control analysis.
Results: Simulation analysis revealed that BDS urine concentration at the time points of hyperhydration was significantly decreased compared to the normal profile; the difference was more pronounced as the hydration level increased. In addition, BDS concentrations below minimum required performance limit (MRPL, 30 ng/mL) resulting in no reportable cases according to WADA guidelines are observed not only after hyperhydration at all hydration levels but even in the normal PK profile. This percentage is approximately 50.0% even for normal PK profile and is probably the result of the circadian rhythm of urine production. The effect of BDS dose and different hyperhydration intake scenarios on BDS PK urine profile is also studied.
Conclusions: Clear effect of hyperhydration on BDS urine profile was shown, supporting the hypothesis of its possible application as a doping masking procedure by athletes. These findings may lead to optimal design of the time schedule of urine sampling during anti-doping control allowing the detection of doping agents if hyperhydration could be used by athletes as a masking procedure. To verify this hypothesis, a single dose BDS PK study in healthy male athletes with or without hyperhydration is designed, based on the present simulation analysis.
References:
[1] Karin Dilger, Jorg Halter, Hartmut Bertz, Luis Lopez-Lazaro, Alois Gratwohl, Jurgen Finke. Pharmacokinetics and Pharmacodynamic Action of Budesonide after Buccal Administration in Healthy Subjects and Patients with Oral Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant 15:336-343, 2009.
[2] I. A. Kechagia, A. Dokoumetzidis. A meta-analysis methodology to estimate population pharmacokinetic parameters from reported non-compartmental values with sparse sampling, 23rd PAGE Meeting, Alicante, Spain, 2014.
[3] Robertson GL, Norgaarg JP. Renal regulation of urine volume: potential implications for nocturia, BJU International 2002, 90:7-10.
[4] Shafiee MA, Charest AF, Cheema-Dhadli S, Glick DN, Napolova O, Roozbeh J, Semenova E, Sharman A, Halperin ML. Defining conditions that lead to the retention of water: The importance of the arterial sodium concentration, Kidney International 2005, 67:613-621.
Reference: PAGE 23 () Abstr 3238 [www.page-meeting.org/?abstract=3238]
Poster: Drug/Disease modeling - Other topics