Population pharmacodynamics for monitoring epoetin in athletes

Epoetin (recombinant human erythropoietin) is used by some endurance athletes to increase oxygen transport and aerobic power in an attempt to improve endurance capacity and recovery during training and competition. Although currently on the list of banned substances issued by the medical commission of the International Olympic Committee, the use of epoetin as an ergogenic agent remains uncontrollable using classical analytical techniques. In the present paper, after subcutaneous administration of repeated high doses (200 units/kg), the pharmacokinetics of epoetin were evaluated in 18 athletes. The mean elimination half-life was 42.0 hours. The total clearance/bioavailability (F) and the volume of distribution/F averaged 0.05 L/h/kg and 2.95 L/kg, respectively. Significant changes in ferritin (fr), soluble transferrin receptor (sTfR) and ratio (sTfR/fr) were observed after administration. A population sigmoidal asymptotic maximum expected effect concentration (e(max)) model has been developed to assess and quantify the relationship between the changes in sTfR, fr and the ratio sTfR/fr secondary to the repeated administration of epoetin. The mean population parameters were as follows: e(max): 12.6 mg/L, 44.9 mu g/L and 2313.5; the concentration producing 50% of the e(max)(C-50): 18.3, 18.1 and 37.7 IU/L; the sigmoidicity factor (gamma): 2.96, 4.17 and 5.15; and keo (rate constant of transfer between central and the effect compartment): 1.29 x 10(-3), 7.14 x 10(-3) and 3.47 x 10(-3)/h for the 3 markers, respectively. Moreover, in this paper, we propose an appropriate statistical methodology based on the measurement of sTfR, fr and sTfR/fr from blood samples to decide if the observed values of these markers could be related, at a given probability risk, to the administration of epoetin. Values greater than 10 mg/L for sTfR and 403 for sTfR/fr indicate a probable intake of epoetin. Because of the large interindividual variability of fr, it has not been possible to define a threshold value for this parameter. The sTfR seems to be the most effective marker in doping control. An increased haematocrit with concomitant changes in sTfR and sTfR/fr values seems to supply a valuable diagnostic tool that avoids false-positive doping and allows the identification of epoetin abusers. Blood samples could be collected using capillary blood from the fingertip or earflap. These controls could be carried out during training because they are easy to perform and do not add substantially to total screening costs. At present, this is the only tool available for detecting epoetin abusers during competition.