Pharmacokinetic evaluation of desogestrel as a female contraceptive.

INTRODUCTION: Desogestrel (DSG) is a third-generation 19-nortestosterone derivative progestogen. It is contained in many oral contraceptive preparations, both combined (COCs) to ethinyl-estradiol (EE) or alone in a progestin-only pill (POP). Its principal metabolite (etonogestrel, ETN) is the only progestin used for intravaginal combined contraception and one of the most used for subdermal hormonal contraception. AREAS COVERED: This is a review of the available data on the pharmacokinetics of DSG and ETN in hormonal contraception. The material included was searched and obtained via Medline, PubMed, and EMBASE up to July 2013 using the search terms 'pharmacokinetics, metabolism' in combination with 'desogestrel, etonogestrel, and progestins.' EXPERT OPINION: DSG and its metabolite ETN are very suitable molecules for use in hormonal contraception. For the oral use the molecule used is DSG, while for parenteral routes (intravaginal, subdermal) its metabolite ETN is the compound of choice. In both cases (oral and parenteral) the active molecule in the organism is the latter (ETN), due to the rapid in vivo metabolism of oral DSG. The contraceptive efficacy and tolerability of all the formulations present on the market (mono/multiphasic EE/DSG COCs, DSG POP, EE/ETN vaginal ring, ETN implant) are reassuring, permitting a long-term use. The estrogenic component increases the contraindications, forcing the prescription to the safer only-progestin preparations, DSG POP or ETN implant.

Pharmacokinetics of a multipurpose pod-intravaginal ring simultaneously delivering five drugs in an ovine model.

Multipurpose technologies that simultaneously protect from sexually transmitted infections and unintended pregnancy are urgently needed. Pod-intravaginal rings (IVRs) formulated with the antiretroviral agents (ARVs) tenofovir, nevirapine, and saquinavir and the contraceptives etonogestrel and estradiol were evaluated in sheep. Steady-state concentrations were maintained for 28 days with controlled, sustained delivery. This proof-of-principle study demonstrates that pod IVRs can deliver three ARVs from different mechanistic classes and a progestin-estrogen combination over the wide range needed for putative preventative efficacy.

St John's wort extract (Ze 117) does not alter the pharmacokinetics of a low-dose oral contraceptive.

PURPOSE: St John's wort (Hypericum perforatum) is an herbal remedy that is widely used in the treatment of depression. Recent clinical data have demonstrated that St John's wort extracts interfere with the action of various drugs and possibly also with combined oral contraceptives. Therefore, we investigated the effects of a St John's wort extract (Ze 117) with low hyperforin content on the pharmacokinetics of ethinylestradiol and 3-ketodesogestrel. METHOD: Sixteen healthy female volunteers, who had taken a low-dose oral contraceptive (Lovelle contains 0.02 mg ethinylestradiol + 0.15 mg desogestrel) for at least 3 months, participated in the study. Pharmacokinetic data (AUC, C(max), t(max)) were determined the day before (reference) and after (test) a 14-day period of Ze 117 intake (250 mg twice daily). RESULTS: Before the co-administration of Ze 117 on day 7, the geometric mean (geometric coefficient of variation) for the AUC(0-24) of ethinylestradiol was 152.53 pg.h/ml (87.39%) and after co-administration on day 21 it was 196.57 pg.h/ml (78.14%). The respective values for ketodesogestrel were 36.37 pg.h/ml (34.18%) and 41.12 pg.h/ml (34.36%). The mean of individual ratios (reference-to-test) of log-transformed AUC values (90% confidence interval) were 0.951 (0.915-0.986) for ethinylestradiol and 0.968 (0.944-0.992) for ketodesogestrel indicating a small gain [corrected] in bioavilability, but bioequivalence nevertheless. CONCLUSION: These results indicate that the recommended dose of the hypericum extract Ze117, which has a low hyperforin content, does not interact with the pharmacokinetics of the hormonal components of the low-dose oral contraceptive.

Interaction of St John's wort with low-dose oral contraceptive therapy: a randomized controlled trial.

AIMS: Breakthrough bleeding or even unwanted pregnancies have been reported in women during concomitant therapy with oral contraceptives and St John's wort extract. The aim of the present study was to investigate the effects of St John's wort extract on oral contraceptive therapy with respect to ovarian activity, breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel. METHODS: Eighteen healthy females were treated with a low-dose oral contraceptive (0.02 mg ethinyloestradiol, 0.150 mg desogestrel) alone (control cycle) or combined with 300 mg St John's wort extract given twice daily (cycle A) or three times daily (cycle B). Ovarian activity was assessed by measuring follicle maturation and serum oestradiol and progesterone concentrations. The number of breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel were assessed under steady-state conditions. RESULTS: During concomitant administration of low-dose oral contraceptive and St John's wort, there was no significant change in follicle maturation, serum oestradiol or progesterone concentrations when compared with oral contraceptive treatment alone. However, significantly more subjects reported intracyclic bleeding during cycles A (13/17 (77%), P < 0.015) and cycle B (15/17 (88%), P < 0.001) than with oral contraceptives alone (6/17 (35%)). The AUC(0,24 h) and Cmax of ethinyloestradiol remained unchanged during all study cycles, whereas the AUC(0,24 h) and Cmax of 3-ketodesogestrel decreased significantly from 31.2 ng ml-1 h to 17.7 ng x ml-1 h (43.9%; 95% confidence interval (CI) -49.3, -38.5, P = 0.001) and from 3.6 ng x ml -1 to 3.0 ng x ml -1(17.8%; CI -29.9, -5.7, P = 0.005), respectively, during cycle A and by 41.7% (CI -47.9, -35.6; P = 0.001) and by 22.8% (CI -31.2, -13.3; P < 0.001) during cycle B respectively, compared with the control cycle. CONCLUSIONS: There was no evidence of ovulation during low-dose oral contraceptive and St John's wort extract combination therapy, but intracyclic bleeding episodes increased. Bleeding irregularities may adversely effect compliance to oral contraceptives and together with St John's wort-induced decreases in serum 3-ketodesogestrel concentrations, enhance the risk of unintended pregnancies.

Release characteristics, ovarian activity and menstrual bleeding pattern with a single contraceptive implant releasing 3-ketodesogestrel.

The properties of a single contraceptive subdermal implant releasing 3-ketodesogestrel were assessed in fifteen women over twelve months. Serum levels of 3-ketodesogestrel were monitored regularly following insertion and after removal. The mean serum level of 3-ketodesogestrel was 245 pg/ml after 72 h (steady state) and 176 pg/ml after twelve months. All volunteers demonstrated ovulation inhibition throughout the study. Transient oestradiol peaks occurred during the study. No luteal activity was noted. The cervical mucus was rapidly rendered hostile to sperm migration. Two women withdrew from the study during the first six months for medical reasons. Both volunteers cited bleeding irregularity as the main cause, one complaining of oligomenorrhoea, the other of prolonged bleeding/spotting episodes. A small but significant increase in weight was noted during the study period.

PIP: 15 sterilized women participated in a clinical trial of the implant Implanon (Organon), a single ethylene vinyl acetate rod containing 60 mg 3-ketodesogestrel (3-KDG), the metabolite of desogestrel. The rod is 40 mm long, 2 mm in diameter and is packaged in its inserter. In this trial the implants were treated to simulate the 2nd year of use. The study subjects underwent intensive hormone and ultrasound monitoring for 72 hours after insertion, twice weekly for 6 weeks and at 6-month intervals. 13 women completed 6 months, 7 completed 12 months, and 5 continued the trial 24 months. There were no complications related to insertion or removal. 3-KDG levels rose to a steady state of 245 pg/ml by 72 hours, then fell to a mean of 17 pg/ml at 12 months. 90 pg/ml of 3-KDG is the critical serum level for anovulation. After removal, 3-KDG declined to 54 pg/ml in 3 days. Follicle development tended toward small follicles or those larger than 10 mm. There was no luteal activity, and LH, FSH and progesterone remained in the follicular phase range. Estradiol levels were not low enough to risk osteoporosis. There was no significant change in serum sex hormone binding globulin. Systolic blood pressure decreased significantly at 12 months; mean weight gain was 3.7 kg (range from loss of 4 kg to gain of 22 kg); a variety of bleeding irregularities were recorded by individual women.