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.
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)).


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 approximately 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 approximately 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.
Terlinden
Rolf
R
Department of Pharmacokinetics, Grünenthal GmbH, D-52099 Aachen, Germany.
Uragg
Heinz
H
Göhler
Karin
K
Kneip
Christa
C
D000293:Adolescent; D000328:Adult; D002250:Carbon Radioisotopes; D002715:Chlormadinone Acetate / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D003280:Contraceptives, Oral, Synthetic / Q000009:adverse effects; D004997:Ethinyl Estradiol / Q000008:administration & dosage* / Q000097:blood; D005243:Feces / Q000737:chemistry; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007553:Isotope Labeling; D007668:Kidney / Q000378:metabolism; D007700:Kinetics
D002250:Carbon Radioisotopes; D003280:Contraceptives, Oral, Synthetic; D002715:Chlormadinone Acetate; D004997:Ethinyl Estradiol