Superior cycle control with a contraceptive vaginal ring compared with an oral contraceptive containing 30 microg ethinylestradiol and 150 microg levonorgestrel: a randomized trial.

BACKGROUND: This trial was conducted to compare cycle control with vaginal ring a combined contraceptive vaginal ring, and a combined oral contraceptive (COC) delivering 30 mug ethinylestradiol (EE) and 150 mug levonorgestrel. METHODS: This open-label, randomized, multi-centre, Phase III study involved adult women from 11 countries. Subjects were treated with either vaginal ring or a COC for 13 cycles (12 months). RESULTS: A total of 1030 subjects (vaginal ring, n=512; COC, n=518) comprised the intention-to-treat (ITT) population. The percentage of women in the ITT population who completed the trial was 70.9% for vaginal ring and 71.2% for the COC group. The incidence of breakthrough bleeding and spotting over cycles 2-13, the primary efficacy parameter, was lower with vaginal ring (range 2.0-6.4%) than the COC (range 3.5-12.6%), and for cycles 2 and 9 the lower incidence with vaginal ring was confirmed as statistically significant (P=0.003 and P=0.002 respectively). The incidence of intended bleeding was significantly higher over all cycles with vaginal ring (58.8-72.8%) than with the COC (43.4-57.9%). CONCLUSIONS: Cycle control with vaginal ring was excellent and superior to that of a COC containing 30 mug EE.

The contraceptive vaginal ring, NuvaRing, and antimycotic co-medication.

We investigated the effect of antimycotic co-medication on the systemic exposure to etonogestrel (ENG) and ethinylestradiol (EE) released from the contraceptive vaginal ring, NuvaRing. Different formulations of miconazole nitrate and single as well as multiple dosing were investigated during two separate randomized, open-label, crossover studies. The first study recruited 12 women to compare the effects of co-use of NuvaRing and a single dose of antimycotic to NuvaRing alone. The second study recruited 14 women to compare the effects of multiple doses of an antimycotic vaginal suppository to an antimycotic vaginal cream equivalent. Co-administration of all three antimycotic formulations resulted in a slight increase in systemic exposure to ENG and EE over time, with suppositories having a more pronounced effect than a cream formulation in the multiple-dosing study. The increases in serum levels observed with the different antimycotic formulations are not expected to compromise NuvaRing's contraceptive efficacy or tolerability.

The in vivo metabolism of tibolone in animal species.

The in vivo tissue distribution and metabolism of tibolone was studied in different animals to further investigate the compound's tissue-specificity. Tibolone's metabolism was studied in vivo in rats and rabbits by administration of [16-3H]-tibolone and the metabolic pattern was determined in urine and faeces after oral administration to female rats and dogs. The main excretory pathway was found to be excretion in the faeces. Important phase-I metabolic routes were the reduction of the 3-keto to the 3a- or 3beta-hydroxy functions with a preference for 3alpha-OH in rats and for 3beta-OH in dogs. To a lesser extent, hydroxylation reactions at C2 and C7, and a shift of the delta5(10)-double bond to a delta4(5)-position also occurred. The main phase-II metabolic route was sulphate conjugation of the hydroxyl groups at C3 and C17. Since the oxidation reactions form only a minor part of the metabolism of tibolone, it is concluded that the cytochrome P450 enzymes do not play an important role in tibolone's metabolism. For both phases, quantitative differences were found between the species. In human similar metabolites are found. Profiling of the target organs in female rats and rabbits showed a tissue-specific distribution of metabolites. The majority of the metabolites existed as sulphate conjugates and no glucuronidated conjugates were observed. The same metabolites were found in both the circulation and the tissues. However, different tissues had quantitatively different metabolic profiles.

Identification of the human P450 enzymes involved in the in vitro metabolism of the synthetic steroidal hormones Org 4060 and Org 30659.

1. The type of human P450 enzymes involved in the in vitro metabolism of Org 4060 and Org 30659, two synthetic steroidal hormones currently under clinical development by NV Organon for use in oral contraceptive and hormone replacement therapy, was investigated. 2. Both steroids were mainly hydroxylated at the 6beta-position in incubations with human liver microsomes. 3. The results from experiments with supersomes, correlation studies as well as inhibition studies with ketoconazole, a selective inhibitor of CYP3A, strongly suggest that the CYP3A family plays a significant role in the 6beta-hydroxylation of both steroids. 4. Measurements of kinetic parameters of P450 enzymes that could metabolize both steroids, combined with the fact that CYP3A4 is known to be the most abundant P450 enzyme in the human liver, indicate that CYP3A4 will be of major importance for the in vivo human metabolism of Org 4060 and Org 30659.

The in vivo human metabolism of tibolone.

In vivo metabolism of tibolone was studied in three healthy postmenopausal volunteers after daily oral administration of 2.5 mg of tibolone for 5 days and a single dose of 2.5 mg approximately equal 555 kBq of [(14)C]tibolone on day 6. The 0- to 192-h recovery of radioactivity in urine and feces was 31.2 +/- 10.5 and 53.7 +/- 5.1%, respectively. Total 0- to 192-h recovery ranged from 78.5 to 94.2% of the dose and averaged 84.9%. Metabolites were putatively identified using high-pressure liquid chromatography in plasma, urine, and feces. The most important phase I metabolic reactions were reduction of the 3-keto group to 3alpha- and 3beta-hydroxy metabolites, a shift of the Delta(5(10))-double bond to a Delta(4(5))-double bond, a reduction of the Delta(4(5))-double bond to 5alpha,10-dihydro or 5beta,10-dihydro metabolites, and hydroxylation at C2 and C7. The most important phase II metabolic reaction is sulfation of the C17 hydroxy group of tibolone and sulfation of the C3 hydroxy groups. In the circulation, over 75% of tibolone and its metabolites are present in the sulfated form. Local metabolism and local sulfatases may contribute to the tissue-specific activity. Using human microsomes, tibolone, 3alpha-hydroxy tibolone, 3beta-hydroxy tibolone, and Delta(4)-tibolone appeared to be at least 50-fold less potent inhibitors of CYP1A2, CYP2C9, CYP2E1, and CYP3A4 compared with enzyme-selective inhibitors. Tibolone and its metabolites, therefore, are not likely to play a clinically significant role at the level of these cytochrome P450 enzymes with regard to the metabolism of coadministered drugs.