### Absorption

Serum concentrations of DRSP reach peak levels approximately 1 hour after administration of ANGELIQ and mean absolute bioavailability of DRSP ranges from 76–85%. Following oral administration, peak serum estradiol concentrations are typically reached 6–8 hours after dosing with ANGELIQ. The oral relative bioavailability of estradiol and DRSP following administration of ANGELIQ is 107% and 102%, respectively when compared to a combination oral suspension. 

The pharmacokinetics of DRSP are dose proportional within the dose range of 0.5–4 mg. Following daily dosing of ANGELIQ, steady state DRSP concentrations were observed after 10 days. Mean accumulation ratios for estradiol and DRSP were 1.9 and 2.4, respectively. Mean concentrations at 2 hours for DRSP ranged between 5.9 and 6.7 ng/mL after treatment with ANGELIQ for 365 days. Mean steady state serum DRSP and E2 concentrations are shown in Figure 1, and a summary of primary pharmacokinetic parameters following the administration of 1mg E2/1mg DRSP for 28 days is presented in Table 1.

Figure 1: Mean steady state serum drospirenone and estradiol concentrations following daily oral administration of 1 mg E2/0.5 mg DRSP11DRSP levels are simulated based on data obtained after oral administration of 1 mg DRSP/1 mg Estradiol

### Effect of Food:

The effect of food on the absorption and bioavailability of DRSP and E2 have not been investigated following the administration of ANGELIQ. However, clinical studies with different formulations containing DRSP or E2 have shown that the bioavailability of both drugs is not affected by concomitant food intake. 

### Distribution 

The mean volume of distribution of DRSP is 4.2 L/kg. DRSP does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG) but binds about 97% to other serum proteins. The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estradiol circulates in the blood bound to SHBG (37%) and to albumin (61%), while only approximately 1%–2% is unbound. 

### Metabolism

Mean clearance of DRSP is 1.2 mL/min/kg. DRSP is extensively metabolized after oral administration. The 2 main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate, both of which are formed without the involvement of the cytochrome P450 system. These metabolites were shown not to be pharmacologically active. In in vitro studies with human liver microsomes, DRSP was metabolized only to a minor extent mainly by Cytochrome P450 3A4 (CYP3A4). 

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. 

### Excretion

DRSP serum levels are characterized by a terminal elimination half-life of approximately 36–42 hours. Excretion of DRSP was nearly complete after 10 days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least 20 different metabolites were observed in urine and feces. About 38% to 47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17% to 20% of the metabolites were excreted as glucuronides and sulfates. Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. 

### Special Populations 

Geriatric: No pharmacokinetic studies were conducted in the geriatric population. 

Pediatric: No pharmacokinetic study for ANGELIQ has been conducted in a pediatric population. 

Gender: ANGELIQ is indicated for use in women only. 

Race: No studies were done to determine the effect of race on the pharmacokinetics of ANGELIQ. 

Patients with Hepatic Impairment: ANGELIQ is contraindicated in patients with hepatic dysfunction (also see BOLDED Warnings). The mean exposure to DRSP in women with moderate liver impairment is approximately three times the exposure in women with normal liver function. 

Patients with Renal Impairment: ANGELIQ is contraindicated in patients with renal insufficiency (also see BOLDED Warnings). 

The effect of renal insufficiency on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the effects of DRSP on serum potassium levels were investigated in female subjects (n = 28, age 30–65) with normal renal function (11 patients), and mild (10 patients) and moderate (7 patients) renal impairment. All subjects were on a low potassium diet. During the study 7 subjects continued the use of potassium-sparing drugs for the treatment of the underlying illness. On the 14th day (steady-state) of DRSP treatment, the serum DRSP levels were on average 37% higher in the group with moderate renal impairment (CLcr 30–50 mL/min) compared to those in the group with normal renal function. Serum DRSP levels in the group with mild renal impairment (creatinine clearance CLcr, 50–80 mL/min) were comparable to those in the group with normal renal function (CLcr, >80 mL/min). DRSP treatment was well tolerated by all groups. DRSP treatment did not show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not observed in the study, in 5 of the 7 subjects who continued use of potassium sparing drugs during the study, individual mean serum potassium levels increased by up to 0.33 mEq/L. Therefore, potential exists for hyperkalemia to occur in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium sparing drugs.