The effects of vilaprisan on the pharmacodynamics and pharmacokinetics of a combined oral contraceptive-A randomized controlled trial.

AIMS: The primary objective was to explore whether the suppression of ovarian activity induced by a combined oral contraceptive (COC) is influenced by the simultaneous intake of the selective progesterone receptor modulator (SPRM) vilaprisan (VPR). METHODS: In this exploratory randomized, double-blind, parallel-group study, 71 healthy premenopausal women were randomized (1:1) to receive either 2 mg/d VPR or placebo for 3 months. Concomitantly, a COC (0.15 mg levonorgestrel, 0.03 mg ethinyloestradiol) was administered in a cyclic regimen. Ovarian activity (Hoogland score based on follicle size and hormone concentrations), cervical function (Insler score), bleeding pattern and endometrial thickness/histology were assessed before treatment, in treatment cycle 3 and during follow-up. RESULTS: The known COC-driven suppression of ovarian activity was mildly affected by VPR. COC+VPR group: 22, 0 and 6% of the subjects had Hoogland scores of 4 (active follicle-like structures), 5 or 6 (ovulation). COC+placebo group: 14% of the subjects had a score of 4 and none a score of 5 or 6 (Bayesian analysis for Hoogland score = 4, median difference in response rate: 7.5%; 90% credible interval [-8.5; 23.5%]). COC effects on cervical function were moderately affected (mucus more sperm permeable under COC+VPR). COC withdrawal bleeding, in contrast, was absent in 81% of the subjects receiving COC+VPR vs 0% receiving COC+placebo. CONCLUSION: The SPRM VPR interfered with the pharmacodynamic effects of the COC. Therefore, full contraceptive effectiveness cannot be assumed without final judgement by a Pearl index study. Women on SPRMs should be advised to use nonhormonal contraception methods.

CYP3A4-mediated effects of rifampicin on the pharmacokinetics of vilaprisan and its UGT1A1-mediated effects on bilirubin glucuronidation in humans.

AIMS: The primary aim of the present study was to quantify the effects of rifampicin, a strong cytochrome P450 (CYP) 3A4 inducer, on the pharmacokinetics of the new selective progesterone receptor modulator, vilaprisan. In addition, the effects of rifampicin on the glucuronidation of bilirubin, an endogenous UDP-glucuronosyltransferase family 1 member A1 (UGT1A1) substrate, were explored. METHODS: This was an open-label, two-period study in 12 healthy postmenopausal women. Subjects received a single oral dose of vilaprisan 4 mg in each period. In period 2, administration of vilaprisan was preceded and followed by rifampicin 600 mg day-1 . A subtherapeutic dose of midazolam (1 mg) was coadministered with vilaprisan to monitor CYP3A4 induction. Details of the administration and sampling schedule were optimized by means of a physiologically based pharmacokinetic model. Plasma concentrations of vilaprisan, midazolam, and 1'- hydroxy-midazolam were measured and rifampicin-associated changes in the glucuronidation of bilirubin were determined. RESULTS: As predicted by our model, the coadministration of rifampicin was associated with a substantial decrease in exposure to vilaprisan and midazolam - indicated by the following point estimates (90% confidence intervals) for the area under the plasma concentration-time curve from zero to the time of the last quantifiable concentration ratio with or without rifampicin: 0.040 (0.0325, 0.0505) for vilaprisan and 0.144 (0.117, 0.178) for midazolam. Further, it was associated with an increase in bilirubin glucuronidation, indicating that UGT1A1 was induced. CONCLUSIONS: The exposure to vilaprisan was reduced by 96%. Such a reduction is likely to render the drug therapeutically ineffective. Therefore, it is recommended that the use of strong CYP3A4 inducers is avoided when taking vilaprisan.

Pharmacokinetics and adhesion of a transdermal patch containing ethinyl estradiol and gestodene under conditions of heat, humidity, and exercise: A single-center, open-label, randomized, crossover study.

In this open-label, randomized study, 36 women (18-45 years) applied an ethinyl estradiol/gestodene contraceptive patch once-weekly for 3 weeks followed by a 1-week, patch-free interval, in 3 treatment periods. The primary objective was to evaluate the pharmacokinetics of ethinyl estradiol and gestodene under conditions of heat, humidity, and exercise. The secondary objective was to evaluate patch adhesion under the same conditions. Weeks 1 and 2 of each period comprised "standardized normal activity" (SNA); in week 3, SNA continued or women used a sauna, whirlpool, swimming pool, or performed an exercise combination. Thirty-one women completed the study; 23 yielded evaluable pharmacokinetic data. Analyses were exploratory and conducted using an analysis of variance. Area under the concentration-time curve from 0 to 168 hours (AUC0-168 ) for gestodene and ethinyl estradiol during sauna, swimming, and whirlpool was equivalent to previous SNA recordings. For exercise combination, the gestodene AUC0-168 was 12% lower compared with SNA, albeit not considered clinically relevant. Two women lost a total of 3 patches during sporting activities; other detachments during this week were not correlated with sporting activity. Overall, hormone delivery using the ethinyl estradiol/gestodene patch under conditions of heat, humidity, and exercise corresponded to delivery under normal conditions.