Comparative pharmacokinetic estimates of drospirenone alone and in combination with ethinyl estradiol after single and repeated oral administration in healthy females

• Published in: Contraception (Stoneham) Vol. 101; no. 2; pp. 137 - 143
• Main Authors: Richter, W.H., Koytchev, R., Kirkov, V., Merki, G., Colli, E., Regidor, P.-A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2020
• Subjects: Administration, Oral; Adult; Androstenes - administration & dosage; Androstenes - pharmacokinetics; Bioavailability; Bulgaria; Cross-Over Studies; Drospirenone; Drug Administration Schedule; Drug Interactions; Ethinyl estradiol; Ethinyl Estradiol - administration & dosage; Ethinyl Estradiol - pharmacokinetics; Female; Humans; Metabolism; Pharmacokinetic; Reproductive Control Agents - pharmacokinetics; Young Adult; Bulgaria; Ethinyl estradiol; Bioavailability; Drospirenone; Metabolism; Pharmacokinetic
• ISSN: 0010-7824; 1879-0518; 1879-0518
• DOI: 10.1016/j.contraception.2019.10.005

To determine the pharmacokinetics (PK) of drospirenone (DRSP), alone versus in combination with ethinyl estradiol (EE), after single and repeated administration. We conducted a single-centre, open-label, crossover, 2-treatment, 2-period, 2-sequence study in which non-micronized DRSP 4 mg or a combination of DRSP 3 mg and EE 0.02 mg were administered to healthy female subjects on day 1 to obtain a single-dose kinetic profile, and from day 4 to day 15 to obtain a repeated-dose kinetic profile. The maximum observed concentration (Cmax) and area under the concentration/time curve (AUC) were determined in a model-independent way using non dose corrected data. Statistical analysis was based on a parametric method (ANOVA-log). A total of 24 healthy female subjects were randomized 1:1 into the study. The mean relative, non-dose-corrected PK estimates after single-dose administration for the endpoints AUC(0-72h), AUC(0-24h) and Cmax were 543.5 ng*h/mL, 296.1 ng*h/mL and 27.3 ng/mL for DRSP alone, and 442.0 ng*h/mL, 264.7 ng*h/mL and 37.5 ng/mL for the DRSP/EE combination; p < 0.001. The mean relative, non-dose-corrected PK estimates after repeated dose administration for the endpoints AUC(0-72h), AUC(0-24h) and Cmax were 1066.8 ng*h/ml, 570.2 ng*h/mL and 41.0 ng/mL for DRSP alone, and 1394.5 ng*h/mL, 732.8 ng*h/mL and 61.4 ng/mL for the DRSP/EE combination; p < 0.001. DRSP alone exhibits a lower accumulation ratio than together with EE. The extent of systemic exposure at steady-state is about 32% less with the new formulation (AUC(0-24h), steady-state geometric mean ratio: 77.8%; 90% confidence interval: 74.6%–81.1%). This PK profile may be caused by EE. Our results suggest that metabolic pathways of DRSP can be inhibited by EE resulting in higher DRSP plasma concentrations in DRSP/EE formulations than in a DRSP-alone formulation. The enzymes CYP3A4 and SULT1A1 may play a role. Additional drug-drug-interaction studies are needed to better understand these metabolic pathways and their future clinical implications.