Pharmacokinetic interaction between the CYP3A4 inhibitor ketoconazole and the hormone drospirenone in combination with ethinylestradiol or estradiol.
OBJECTIVE
The present study was conducted to investigate the influence of the strong CYP3A4 inhibitor ketoconazole (KTZ) on the pharmacokinetics of drospirenone (DRSP) administered in combination with ethinylestradiol (EE) or estradiol (E2).


METHODS
This was a randomized, multicentre, open label, one way crossover, fixed sequence study with two parallel treatment arms. A group sequential design allowed terminating the study for futility after first study cohort. About 50 healthy young women were randomized 1 : 1 to 'DRSP/EE' or 'DRSP/E2'. Subjects in the 'DRSP/EE' group received DRSP 3 mg/EE 0.02 mg (YAZ®, Bayer) once daily for 21 to 28 days followed by DRSP 3 mg/EE 0.02 mg once daily plus KTZ 200 mg twice daily for 10 days. Subjects in the 'DRSP/E2' group received DRSP 3 mg/E2 1.5 mg (research combination) once daily for 21 to 28 days followed by DRSP 3 mg/E2 1.5 mg once daily plus KTZ 200 mg twice daily for 10 days.


RESULTS
Oral co-administration of DRSP/EE or DRSP/E2 and KTZ resulted in an increase in DRSP exposure (AUC(0,24 h)) in both treatment groups: DRSP/EE group: 2.68-fold DRSP increase (90% CI 2.44, 2.95); DRSP/E2 group: 2.30-fold DRSP increase (90% CI 2.08, 2.54). EE and estrone (metabolite of E2) exposures were increased ~1.4-fold whereas E2 exposure was largely unaffected by KTZ co-administration.


CONCLUSIONS
A moderate pharmacokinetic drug-drug interaction between DRSP and KTZ was demonstrated in this study. No relevant changes of medical concern were detected in the safety data collected in this study.
Bayer Pharma AG, Berlin.
Herbert
H
Wiesinger
CRS Clinical Research Services Berlin GmbH, Berlin.
Matthias
M
Berse
Bayer Pharma AG, Berlin.
Stefan
S
Klein
Bayer Pharma AG, Berlin.
Simone
S
Gschwend
Bayer Pharma AG, Berlin.
Joachim
J
Höchel
Pharma Consult, Berlin, Germany.
Frank S
FS
Zollmann
Bayer Pharma AG, Berlin.
Barbara
B
Schütt
D000328:Adult; D000736:Androstenes / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D004958:Estradiol / Q000493:pharmacokinetics*; D004997:Ethinyl Estradiol / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008875:Middle Aged
D000736:Androstenes; D065692:Cytochrome P-450 CYP3A Inhibitors; C534342:drospirenone and ethinyl estradiol combination; D004997:Ethinyl Estradiol; D004958:Estradiol; C035144:drospirenone; D007654:Ketoconazole
contraception; cytochrome P-450 CYP3A4 inhibitors; drospirenone; drug interactions; ethinyl estradiol; hormone replacement therapy