Jastinda Mechanism of Action

Pharmacotherapeutic group: Progestogens and estrogens, fixed combinations. ATC code: G03AA12.
Pharmacodynamics: Pearl Index for method failure: 0.41 (upper two-sided 95% confidence limit: 0.85).
The contraceptive effect of JASTINDA is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the endometrium.
JASTINDA is a combined oral contraceptive with ethinylestradiol and the progestogen drospirenone. In a therapeutic dosage, drospirenone also possesses antiandrogenic and mild antimineralocorticoid properties. It has no estrogenic, glucocorticoid and antiglucocorticoid activity. This gives drospirenone a pharmacological profile closely resembling the natural hormone progesterone.
There are indications from clinical studies that the mild antimineralocorticoid properties of drospirenone/ethinylestradiol result in a mild antimineralocorticoid effect.
Pharmacokinetics: Drospirenone: Absorption: Orally administered drospirenone is rapidly and almost completely absorbed. Maximum concentrations of the active substance in serum of about 35 ng/ml are reached at about 1-2 h after single ingestion. Bioavailability is between 76 and 85%. Concomitant ingestion of food has no influence on the bioavailability of drospirenone.
Distribution: After oral administration, serum drospirenone levels decrease in two phases which are characterized by half-lives of 1.6 ± 0.7 h and 27.0 ± 7.5 h, respectively. Drospirenone is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). Only 3-5% of the total serum concentrations of the active substance are present as free steroid. The ethinylestradiol-induced increase in SHBG does not influence the serum protein binding of drospirenone. The mean apparent volume of distribution of drospirenone is 3.7 ± 1.2 l/kg.
Biotransformation: Drospirenone is extensively metabolized after oral administration. The major metabolites in the plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4, 5-dihydro-drospirenone-3-sulfate, both of which are formed without involvement of the P₄₅₀ system. Drospirenone is metabolized to a minor extent by cytochrome P450 3A4 and has demonstrated a capacity to inhibit this enzyme and cytochrome P₄₅₀ 1A1, cytochrome P₄₅₀ 2C9 and cytochrome P₄₅₀ 2C19 in vitro.
Elimination: The metabolic clearance rate of drospirenone in serum is 1.5 ± 0.2 ml/min/kg. Drospirenone is excreted only in trace amounts in unchanged form. The metabolites of drospirenone are excreted with the faeces and urine at an excretion ratio of about 1.2 to 1.4. The half-life of metabolite excretion with the urine and faeces is about 40 h.
Steady-state conditions: During a treatment cycle, maximum steady-state concentrations of drospirenone in serum of about 60 ng/ml are reached between day 7 and day 14 of treatment. Serum drospirenone levels accumulated by a factor of about 2 to 3 as a consequence of the ratio of terminal half-life and dosing interval. Further accumulation of drospirenone levels beyond treatment cycles was observed between cycles 1 and 6 but thereafter, no further accumulation was observed.
Special populations: Effect of renal impairment: Steady-state serum drospirenone levels in women with mild renal impairment (creatinine clearance CL_cr,50-80 ml/min) were comparable to those of women with normal renal function. The serum drospirenone levels were on average 37% higher in women with moderate renal impairment (CL_cr,30-50 ml/min) compared to those in women with normal renal function. Drospirenone treatment was also well tolerated by women with mild and moderate renal impairment. Drospirenone treatment did not show any clinically significant effect on serum potassium concentration.
Effect of hepatic impairment: JASTINDA is contraindicated in patients with hepatic dysfunction (see Contraindications). The mean exposure to drospirenone in women with moderate liver impairment is approximately three times the exposure in women with normal liver function. JASTINDA has not been studied in women with severe hepatic impairment.
Ethnic groups: No clinically relevant differences in the pharmacokinetics of drospirenone or ethinylestradiol between Japanese and Caucasian women have been observed.
Ethinylestradiol: Absorption: Orally administered ethinylestradiol is absorbed rapidly and completely. Peak serum concentrations of about 88 to 100 pg/ml are reached within 1 - 2 hours after single oral administration. During absorption and first-liver passage, ethinylestradiol is metabolized extensively, resulting in a mean oral bioavailability of about 45% with a large interindividual variation of about 20-65%. Concomitant intake of food reduced the bioavailability of ethinylestradiol in about 25% of the investigated subjects while no change was observed in the others.
Distribution: Serum ethinylestradiol levels decrease in two phases, the terminal disposition phase is characterized by a half-life of approximately 24 hours. Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98.5%), and induces an increase in the serum concentrations of SHBG and corticoid binding globulin (CBG). An apparent volume of distribution of about 5 l/kg was determined.
Biotransformation: Ethinylestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolized by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucuronides and sulfate. The metabolic clearance rate of ethinylestradiol is about 5 ml/min/kg.
Elimination: Ethinylestradiol is not excreted in unchanged form to any significant extent. The metabolites of ethinylestradiol are excreted at a urinary to biliary ratio of 4:6.The half-life of metabolite excretion is about 1 day.
Steady-state conditions: Steady-state conditions are reached during the second half of a treatment cycle and serum levels of ethinylestradiol accumulate by a factor of about 1.4 to 2.1.
Toxicology: Preclinical safety data: Predinical data reveal no special risks for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. In laboratory animals, the effects of drospirenone and ethinylestradiol were confined to those associated with the recognized pharmacological action. In particular, reproduction toxicity studies revealed embryotoxic and foetotoxic effects in animals which are considered as species specific.
Ethinylestradiol-induced tumours in rodents have previously been seen with other ethinylestradiol-containing products, and are considered attributable to species-specific effects of estrogens on prolactin secretion in rodents. Although long-term animal studies did not definitely indicate a tumourigenic potential for the clinical use of either drospirenone or ethinylestradiol, it should be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumours.