Multiple-dose pharmacokinetics of atrasentan, an endothelin-A receptor antagonist

Objective: To determine the single- and multiple-dose pharmacokinetics of atrasentan, a highly selective endothelin-A receptor antagonist that is currently being investigated for the treatment of prostate cancer and cardiovascular disorders. Design: Phase I, randomised, placebo-controlled, double-blind, single- and multiple-dose study of orally administered atrasentan. Methods: Single daily oral doses of 1, 5, 10, 15, 20, 25, 30 or 40mg of atrasentan or placebo were administered to healthy male volunteers (n = 72; six active and three placebo per drug administration group) on study day 1 and days 3 to 9. Atrasentan plasma concentration-time profiles for day 1 and day 9 were used to assess atrasentan pharmacokinetics. Results: Except for the 1mg group, atrasentan plasma concentrations increased rapidly after single and multiple administration, declining thereafter biexponentially with a study-wide harmonic mean (pseudo-SD) half-life of 21 (12) hours and mean (SD) apparent total body clearance (CL/F) of 28 (9.8) L/h. For the 1mg group, there was no apparent distribution phase and the absorption was slower. Drug administration in the 40mg group was discontinued prematurely because of adverse events. Except for lower-than-predicted maximum plasma concentration (C-max) values for the 1mg group, drug exposure (Cmax, trough concentration and area under the concentration-time curve) increased linearly with dose, and CL/F values were similar across groups, after single- and multiple-dose administration. Steady state was reached within 4 days of drug administration. Conclusion: The pharmacokinetics of atrasentan are dose- and time-independent after single- and multiple-dose administration over the range of 1 to 30 mg/day.