Pharmacokinetics of chlormadinone acetate following single and multiple oral dosing of chlormadinone acetate (2 mg) and ethinylestradiol (0.03 mg) and elimination and clearance of a single dose of radiolabeled chlormadinone acetate

Abstract

Background Published data on pharmacokinetic parameters for chlormadinone acetate (CMA) are in part contradictory, especially with regard to terminal half-life ( t 1/2, z ). Materials and Methods Single and multiple doses of CMA (2 mg) and ethinylestradiol (EE; 0.03 mg) were administered to healthy female volunteers for six menstrual cycles. Plasma concentrations of CMA and EE were determined by gas chromatography–mass spectrometry. Single-dose and steady-state pharmacokinetic parameters were calculated. In a separate study, healthy female volunteers were given a single 2-mg dose of radiolabeled CMA. Concentrations of radioactivity in fecal and urine samples were determined via liquid scintillation. Excretion of total radioactivity was calculated as percentage of administered dose. Results Eighteen women completed the repeated-dose study. Peak plasma concentrations for CMA and EE were reached within 1 and 2 h after taking the study drug. Peak plasma concentrations of CMA were ∼1600 pg/mL after single-dose administration and 2000 pg/mL after multiple dosing. CMA and EE showed linear pharmacokinetics throughout six cycles, with constant trough values of ∼400–500 pg/mL for CMA and 20–40 pg/mL for EE. Mass balance factors were 1.2–1.4 for CMA and 1.6–1.7 for EE, and accumulation factors were 1.7–2 for CMA and 1.7–1.8 for EE. Mean t 1/2, z of CMA was approximately 25 h after single dosing and 36–39 h at steady state. In the excretion balance study, mean dose of CMA recovered was 87.3±6.4%, with urinary and fecal excretion accounting for 45% and 42%, respectively. Conclusions The pharmacokinetics of CMA and EE is linear after multiple dosing and remains stable during long-term administration, once steady state is reached. The t 1/2, z of CMA was 36–39 h after multiple dosing, which is considerably shorter than the 80 h often quoted in the literature.