Etonogestrel

The etonogestrel implant is a non-biodegradable, radiopaque, etonogestrel-containing implant for subdermal use, preloaded in a sterile, disposable applicator. Etonogestrel is the biologically active metabolite of desogestrel, a progestagen widely used in OCs. It is structurally derived from 19-nortestosterone and binds with high affinity to progesterone receptors in the target organs. The contraceptive effect of etonogestrel is primarily achieved by inhibition of ovulation. Ovulations were not observed in the first two years of use of the implant and only rarely in the third year. Besides inhibition of ovulation, etonogestrel also causes changes in the cervical mucus, which hinders the passage of spermatozoa.

Absorption

After the insertion of the implant, etonogestrel is rapidly absorbed into the circulation. Ovulation-inhibiting concentrations are reached within 1 day. Maximum serum concentrations (between 472 and 1,270 pg/ml) are reached within 1 to 13 days. The release rate of the implant decreases with time. As a result, serum concentrations decline rapidly over the first few months. By the end of the first year, a mean concentration of approximately 200 pg/ml (range 150-261 pg/ml) is measured, which slowly decreases to 156 pg/ml (range 111-202 pg/ml) by the end of the third year. The variations observed in serum concentrations can be partly attributed to differences in body weight.

Distribution

Etonogestrel is 95.5-99% bound to serum proteins, predominantly to albumin and to a lesser extent to sex hormone binding globulin. The central and total volumes of distribution are 27l and 220l, respectively, and hardly change during the use of etonogestrel.

Biotransformation

Etonogestrel undergoes hydroxylation and reduction. Metabolites are conjugated to sulfates and glucuronides. Animal studies show that enterohepatic circulation probably does not contribute to the progestagenic activity of etonogestrel.

Elimination

After intravenous administration of etonogestrel, the mean elimination half-life is approximately 25 hours and the serum clearance is approximately 7.5 l/hour. Both clearance and elimination-half-life remain constant during the treatment period. The excretion of etonogestrel and its metabolites, either as free steroids or as conjugates, is with urine and faeces (ratio 1.5:1). After insertion in lactating women, etonogestrel is excreted in breast milk with a milk/serum ratio of 0.44-0.50 during the first four months. In lactating women, the mean transfer of etonogestrel to the infant is approximately 0.2% of the estimated absolute maternal etonogestrel daily dose (2.2% when values are normalised per kg body weight). Concentrations show a gradual and statistically significant decrease over time.

Toxicological studies did not reveal any effects other than those, which can be explained on the basis of the hormonal properties of etonogestrel, regardless of the route of administration.