Pharmacokinetic profile of nomegestrol acetate and 17β-estradiol after multiple and single dosing in healthy women

Gerrits, Mireille; Schnabel, Peter; Post, Teun M.; Peeters, Pierre

doi:10.1016/j.contraception.2012.07.001

Cited by 33 publications

(35 citation statements)

References 35 publications

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“…While MPA, NES, NoMAC and DRSP do not bind to SHBG and are 100% available, NET-A, LNG and GES can bind and the availability of these progestins is approximately 65%, 50% and 25%, respectively [2,34,35]. Considering the above, and the affinities of DHT and the progestins for the AR, plus the fact that the progestin EC 50 values for the AR in our study are within the range of serum concentrations reported for MPA (0.2 – 65 nM) [13], NET-A (17.6 – 36 nM) (Jinteli package insert, Teva Pharmaceuticals USA Inc.), LNG (4.4 – 16 nM) [36], GES (6.4 – 31 nM) [36], NES (0.1 – 27.3 nM) [37], NoMAC (3 – 33 nM) [38] and DRSP (26.7 – 253 nM) [39], it is likely that the progestins will compete with DHT for binding to the AR in vivo . However, considering the affinities of the progestins and E 2 for ERα, and that the EC 50 values determined for NET-A, LNG and GES are 10 to 100-fold lower than the serum concentrations mentioned above, it is unlikely that these progestins will compete with E 2 for binding to ERα in target tissues.…”

Section: Discussionmentioning

confidence: 99%

Comparing the androgenic and estrogenic properties of progestins used in contraception and hormone therapy

Toit

Perkins

Hapgood

et al. 2017

Biochemical and Biophysical Research Communications

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Progestins used in endocrine therapies bind to multiple steroid receptors and are associated with several side-effects. It is thus important to understand the relationship between steroid receptor cross-reactivity and the side-effect profile of progestins. In cell lines that express negligible levels of steroid receptors, we report for the first time the binding affinities, potencies and efficacies of selected progestins from different generations determined in parallel. We show that the progestins bind to the androgen receptor (AR) with similar affinities to each other and progesterone, while none bind estrogen receptor (ER)-β, and only norethisterone acetate, levonorgestrel and gestodene bind ERα. Comparative dose-response analysis revealed that progestins from the first three generations display similar androgenic activity to the natural androgen dihydrotestosterone for transactivation, while norethisterone acetate, levonorgestrel and gestodene are ERα agonists. We show for the first time that the anti-androgenic properties of progesterone and drospirenone are similar to the well-known AR antagonist hydroxyflutamide, while nomegestrol acetate is more potent and nestorone less potent than both hydroxyflutamide and progesterone. Moreover, we are the first to report that the older progestins, unlike progesterone and the fourth generation progestins, are efficacious ERα agonists for transrepression, while the selected progestins from the second and third generation are efficacious AR agonists for transrepression. Considering the progestin potencies and their reported free serum concentrations relative to dihydrotestosterone and estradiol, our results suggest that the progestins are likely to exert AR-, but not ERα- or ERβ-mediated effects in vivo.

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Section: Discussionmentioning

confidence: 99%

Comparing the androgenic and estrogenic properties of progestins used in contraception and hormone therapy

Toit

Perkins

Hapgood

et al. 2017

Biochemical and Biophysical Research Communications

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“…The oral bioavailability of NOMAC is considered to be relatively high, at about 65% 9. Peak serum levels of NOMAC are rapidly seen 9,10,22. NOMAC has a long elimination half-life (45–50 hours) compared with other contraceptive progestins.…”

Section: Pharmacology Mechanism Of Action and Pharmacokineticsmentioning

confidence: 99%

“…The bioavailability of E2 is between 1% and 5% 10,22. Once ingested, estradiol is metabolized by the liver to estrone and estrone sulfate, among other compounds.…”

Section: Pharmacology Mechanism Of Action and Pharmacokineticsmentioning

confidence: 99%

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Nomegestrol acetate-17b-estradiol for oral contraception

Burke¹

2013

PPA

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Oral contraceptives remain a popular method of contraception over 50 years after their introduction. While safe and effective for many women, the failure rate of oral contraception is about 8%. Concerns about the risk of venous thromboembolism continue to drive the search for the safest oral contraceptive formulations. The oral contraceptive NOMAC-E2 contains nomegestrol acetate (NOMAC) 2.5 mg + 17b-estradiol (E2) 1.5 mg. The approved dosing regimen is 24 days of active hormone, followed by a 4-day hormone-free interval. NOMAC is a progestin derived from testosterone, which has high bioavailability, rapid absorption, and a long half-life. Estradiol, though it has a lower bioavailability, has been successfully combined with NOMAC in a monophasic oral contraceptive. Two recently published randomized controlled trials demonstrate that NOMAC-E2 is an effective contraceptive, with a Pearl Index less than one pregnancy per 100 woman-years. The bleeding pattern on NOMAC-E2 is characterized by fewer bleeding/spotting days, shorter withdrawal bleeds, and a higher incidence of amenorrhea than the comparator oral contraceptive containing drospirenone and ethinyl estradiol. The adverse event profile appears to be acceptable. Few severe adverse events were reported in the randomized controlled trials. The most common adverse events were irregular bleeding, acne, and weight gain. Preliminary studies suggest that NOMAC-E2 does not seem to have negative effects on hemostatic and metabolic parameters. While no one oral contraceptive formulation is likely to be the optimum choice for all women, NOMAC-E2 is a formulation with effectiveness comparable with that of other oral contraceptives, and a reassuring safety profile.

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“…After that, Christin-Maitre and colleagues23 compared the 1.5 mg E2/2.5 mg NOMAC in a 21/7 and 24/4 regimen and found that while neither regimen was associated with anovulation, the 24/4 regimen was associated with greater inhibition of follicular growth and a shorter duration of withdrawal bleeding, suggesting that the 24/4 regimen of E2/NOMAC would be associated with a greater margin of contraceptive effectiveness and a more tolerable and acceptable bleeding profile with fewer symptoms attributable to the hormone-free interval and acute hormone withdrawal. More recently, Gerrits and colleagues showed that the 1.5 mg E2/2.5 mg NOMAC administered for 24 days has a pharmacokinetic profile consistent with once-daily dosing,24 With the dosing and regimen studies complete, a comparative study of the impact of 1.5 mg E2/2.5 mg NOMAC 24/4 (Zoely ® , Merck & Co., Inc, Whitehouse Station, NJ, USA) on ovulation to that of a popular oral contraceptive regimen containing 30 µg EE/3 mg drospirenone (DRSP) (Yasmin ® , Bayer Pharmaceuticals, Berlin, Germany) was undertaken 25. Duijkers and colleagues found that no ovulations occurred among the 48 women randomised (2 E2/NOMAC:1 EE/DRSP) to one of the two regimens and that the suppressive effect of E2/NOMAC, as evaluated by ultrasound measurement of follicular diameter, was similar to that observed with users of EE/DRSP.…”

Section: E2/nomac Combination Oral Contraceptionmentioning

confidence: 99%

Changing convention in combination oral contraceptives: estradiol and nomegestrol acetate in a monophasic 24/4 regimen

Shulman

2013

J Fam Plann Reprod Health Care

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Initial oral contraceptive regimens were characterised by high doses of ethinylestradiol (EE) and a progestogen in a 21-day regimen that either included seven additional hormone-free tablets or simply the 21 days of combination hormonal tablets. These regimens were developed to ensure high contraceptive effectiveness, regular and predictable withdrawal bleeding episodes to mimic a menstrual cycle, and minimal unscheduled vaginal bleeding. However, these regimens were associated with adverse tolerability and safety issues resulting from the dose and characteristics of their hormonal components. Attempts to ameliorate these adverse issues included the development of lower-dose EE regimens, the incorporation of new progestogens, multiphasic regimens, and reduced hormone-free interval regimens. However, the EE component has remained a constant until the recent approval of combination oral contraceptives with an estrogen component other than EE. The development and introduction of an estradiol-based oral contraceptive regimen is presented in this review.

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Pharmacokinetic profile of nomegestrol acetate and 17β-estradiol after multiple and single dosing in healthy women

Cited by 33 publications

References 35 publications

Comparing the androgenic and estrogenic properties of progestins used in contraception and hormone therapy

Comparing the androgenic and estrogenic properties of progestins used in contraception and hormone therapy

Nomegestrol acetate-17b-estradiol for oral contraception

Changing convention in combination oral contraceptives: estradiol and nomegestrol acetate in a monophasic 24/4 regimen

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