CLINICAL PHARMACOLOGY

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

Receptor binding studies, as well as studies in animals, have shown that etonogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity (91, 92). The relevance of this latter finding in humans is unknown.

Pharmacokinetics

Absorption

Desogestrel is rapidly and almost completely absorbed and converted into etonogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel compared to a solution, as measured by serum levels of etonogestrel, is approximately 100%. Desogestrel and Ethinyl Estradiol Tablets, USP and Ethinyl Estradiol Tablets, USP provide two different regimens of ethinyl estradiol; 0.02 mg in the combination tablet [white] as well as 0.01 mg in the yellow tablet. Ethinyl estradiol is rapidly and almost completely absorbed. After a single dose of Desogestrel and Ethinyl Estradiol Tablets, USP and Ethinyl Estradiol Tablets, USP combination tablet [white], the relative bioavailability of ethinyl estradiol is approximately 93% while the relative bioavailability of the 0.01 mg tablet [yellow] is 99%. The effect of food on the bioavailability of Desogestrel and Ethinyl Estradiol Tablets, USP and Ethinyl Estradiol Tablets, USP following oral administration has not been evaluated.

The pharmacokinetics of etonogestrel and ethinyl estradiol following multiple dose administration of Desogestrel and Ethinyl Estradiol Tablets, USP and Ethinyl Estradiol Tablets, USP were determined during the third cycle in 17 subjects. Plasma concentrations of etonogestrel and ethinyl estradiol reached steady state by Day 21. The AUC(024) for etonogestrel at steady state on Day 21 was approximately 2.2 times higher than AUC(024) on Day 1 of the third cycle. The pharmacokinetic parameters of etonogestrel and ethinyl estradiol during the third cycle following multiple dose administration of Desogestrel and Ethinyl Estradiol Tablets, USP and Ethinyl Estradiol Tablets, USP are summarized in Table I.

TABLE I: MEAN (SD) PHARMACOKINETIC PARAMETERS OF Desogestrel and Ethinyl Estradiol Tablets, USP and Ethinyl Estradiol Tablets, USP OVER A 28 DAY DOSING PERIOD IN THE THIRD CYCLE (n = 17).

Etonogestrel

Day	Dose a mg	C max pg/mL	T max h	t 1/2 h	AUC 0-24 pg/mL.hr	CL/F L/h
1	0.15	2503.6(987.6)	2.4 (1.0)	29.8(16.3)	17,832(5674)	5.4(2.5)
21	0.15	4091.2(1186.2)	1.6(0.7)	27.8(7.2)	39,391(12,134)	4.4(1.4)

a) Desogestrel

Ethinyl Estradiol

Day	Dose a mg	C max pg/mL	Tmax h	t 1/2 h	AUC 0-24 pg/mL.hr	CL/F L/h
1	0.02	51.9(15.4)	2.9(1.2)	16.5 (4.8)	566 (173) a	25.7 (9.1)
21	0.02	62.2 (25.9)	2.0(0.8)	23.9 (25.5)	597 (127) a	35.1 (8.2)
24	0.01	24.6(10.8)	2.4(1.0)	18.8 (10.3)	246 (65)	43.6 (12.2)
28	0.01	35.3(27.5)	2.1(1.3)	18.9 (8.3)	312 (62)	33.2 (6.6)
C max – measured peak concentration
T max – observed time of peak concentration
t 1/2 – elimination half-life, calculated by 0.693/K elim
AUC 0-24 – area under the concentration-time curve calculated by the linear trapezoidal rule (Time 0 to 24 hours)
CL/F – apparent clearance

a) n=16

Distribution

Etonogestrel, the active metabolite of desogestrel, was found to be 99% protein bound, primarily to sex hormone-binding globulin (SHBG). Ethinyl estradiol is approximately 98.3% bound, mainly to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis. Desogestrel, in combination with ethinyl estradiol, does not counteract the estrogen-induced increase in SHBG, resulting in lower serum levels of free testosterone (96 to 99).

Metabolism

Desogestrel:

Desogestrel is rapidly and completely metabolized by hydroxylation in the intestinal mucosa and on first pass through the liver to etonogestrel. Other metabolites (i.e., 3-OH-desogestrel, 3-OH-desogestrel, and 3-OH-5-H-desogestrel) with no pharmacologic actions also have been identified and these metabolites may undergo glucuronide and sulfate conjugation.

Ethinyl Estradiol:

Ethinyl estradiol is subject to a significant degree of presystemic conjugation (phase II metabolism). Ethinyl estradiol escaping gut wall conjugation undergoes phase I metabolism and hepatic conjugation (phase II metabolism). Major phase I metabolites are 2-OH-ethinyl estradiol and 2-methoxy-ethinyl estradiol. Sulfate and glucuronide conjugates of both ethinyl estradiol and phase I metabolites, which are excreted in bile, can undergo enterohepatic circulation.

Excretion

Etonogestrel and ethinyl estradiol are excreted in urine, bile, and feces. At steady state, on Day 21, the elimination half-life of etonogestrel is 27.8 ± 7.2 hours and the elimination half-life of ethinyl estradiol for the combination tablet is 23.9 ± 25.5 hours. For the 0.01 mg ethinyl estradiol tablet [yellow], the elimination half-life at steady state, Day 28, is 18.9 ± 8.3 hours.

Special Populations

Race

There is no information to determine the effect of race on the pharmacokinetics of Desogestrel and Ethinyl Estradiol Tablets, USP and Ethinyl Estradiol Tablets, USP.

Hepatic Insufficiency

No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of Desogestrel and Ethinyl Estradiol Tablets, USP and Ethinyl Estradiol Tablets, USP.

Renal Insufficiency

No formal studies were conducted to evaluate the effect of renal disease on the disposition of Desogestrel and Ethinyl Estradiol Tablets, USP and Ethinyl Estradiol Tablets, USP.

Drug-Drug Interactions

Interactions between desogestrel/ethinyl estradiol and other drugs have been reported in the literature. No formal drug-drug interaction studies were conducted (see PRECAUTIONS).