Ovupic Mechanism of Action

Aromatase Inhibitor.
Pharmacology: Pharmacodynamics: The elimination of Estrogen-mediated growth stimulation is a prerequisite for tumor response in cases where the growth of tumor tissue depends on the presence of Estrogens and endocrine therapy is used. In postmenopausal women, Estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens - primarily androstenedione and testosterone - to Estrone and Estradiol. The suppression of Estrogen biosynthesis in peripheral tissues and the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.
Letrozole is a non-steroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively binding to the heme of the aromatase cytochrome P450, resulting in a reduction of Estrogen biosynthesis in all tissues where present.
In healthy postmenopausal women, single doses of 0.1 mg, 0.5 mg and 2.5 mg Letrozole suppress serum estrone and estradiol by 75%, 78% and 78% from baseline respectively. Maximum suppression is achieved in 48-78 hours.
In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg suppressed plasma concentration of Estradiol, Estrone, and Estrone sulphate by 75-95% from baseline in all patients treated. With doses of 0.5 mg and higher, many values of Estrone and Estrone sulphate were below the limit of detection in the assays, indicating that higher Estrogen suppression is achieved with these doses. Estrogen suppression was maintained throughout treatment in all these patients.
Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, and ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of Letrozole 0.1 to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Thus, glucocorticoid and mineralocorticoid supplementation is not necessary.
No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1 mg, 0.5 mg, and 2.5 mg single doses of Letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 mg to 5 mg, indicating that the blockade of Estrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH are not affected by Letrozole in patients, nor is thyroid function as evaluated by TSH, T4 and T3 uptake test.
Pharmacokinetics: Absorption: Letrozole is rapidly and completely absorbed from the gastrointestinal tract (mean absolute bioavailability: 99.9%). Food slightly decreases the rate of absorption (median t_max 1 hour fasted versus 2 hours fed; and mean C_max 129±20.3 nmol/liter fasted versus 98.7±18.6 nmol/liter fed) but the extent of absorption (AUC) is not changed. The minor effect on the absorption rate is not considered to be of clinical relevance, and therefore Letrozole may be taken without regard to mealtimes.
Distribution: Plasma protein binding of Letrozole is approximately 60%, mainly to albumin (55%). The concentration of Letrozole in erythrocytes is about 80% of that in plasma. After administration of 2.5 mg ¹⁴C-labelled Letrozole, approximately 82% of the radioactivity in plasma was unchanged compound. Systemic exposure to metabolites is therefore low. Letrozole is rapidly and extensively distributed to tissues. Its apparent volume of distribution at steady state is about 1.87±0.47 L/kg.
Biotransformation: Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination pathway of Letrozole (CL_m=2.1 L/h) but is relatively slow when compared to hepatic blood flow (about 90 L/h). The cytochrome P450 isoenzymes 3A4 and 2A6 were found to be capable of converting Letrozole to this metabolite. In vitro, but their individual contributions to Letrozole clearance in vivo have not been established. In an interaction study coadministration with cimetidine, which is known to inhibit only the 3A4 isoenzyme, did not result in a decrease in Letrozole clearance suggesting that in vivo the 2A6 isoenzyme plays an important part in total clearance.
Formation of minor unidentified metabolites and direct renal and fecal excretion play only a minor role in the overall elimination of Letrozole. Within 2 weeks after administration of 2.5 mg ¹⁴C-labelled Letrozole to healthy postmenopausal volunteers, 88.2±7.6% of the radioactivity was recovered in urine and 3.8±0.9% in feces. At least 75% of the radioactivity recovered in urine up to 216 hours (84.7±7.8% of the dose) was attributed to the glucuronide of the carbinol metabolite, about 9% to two unidentified metabolites, and 6% to unchanged Letrozole.
Elimination: The apparent terminal elimination half-life in plasma is about 2 to 4 days. After daily administration of 2.5 mg steady-state levels are reached within 2 to 6 weeks. Plasma concentrations at steady-state are approximately 7 times higher than concentrations measured after a single dose of 2.5 mg, while they are 1.5 to 2 times higher than the steady-state values predicted from the concentrations measured after a single dose, indicating a slight non-linearity in the pharmacokinetics of Letrozole upon daily administration of 2.5 mg. Since steady-state levels are maintained over time, it can be concluded that no continuous accumulation of Letrozole occurs.
Linearity/non-linearity: The pharmacokinetics of Letrozole were dose proportional after single oral doses up to 10 mg (dose range: 0.01 to 30 mg) and after daily doses up to 1.0 mg (dose range: 0.1 to 5 mg). After a 30 mg single oral dose there was a slightly dose over-proportional increase in AUC value. The dose over-proportionality is likely to be the result of a saturation of metabolic elimination processes. Steady levels were reached after 1 to 2 months at all dosage regimens tested (0.1-5.0 mg daily).
Special populations: Elderly: Age had no effect on the pharmacokinetics of Letrozole.
Renal impairment: In a study involving 19 volunteers with varying degrees of renal function (24-hour creatinine clearance 9-116 mL/min) no effect on the pharmacokinetics of Letrozole or the urinary excretion of the glucuronide of its carbinol metabolite was found after a single dose of 2.5 mg. In addition to the previously mentioned study assessing the influence of renal impairment on Letrozole, a covariate analysis was performed on the data of two pivotal studies (Study AR/BC2 and Study AR/BC3). Calculated creatinine clearance (ClCr) [Study AR/BC2 range: 19 to 187 mL/min; Study AR/BC3 range: 10 to 180 mL/min] showed no statistically significant association between Letrozole plasma trough levels at steady-state (C_min). Furthermore, data of Study AR/BC2 and Study AR/BC3 in second-line metastatic breast cancer showed no evidence of an adverse effect of Letrozole on ClCr or an impairment of renal function.
Therefore, no dose adjustment is required for patients with renal impairment (ClCr ≥10 mL/min). Little information is available in patients with severe impairment of renal function (ClCr <10 mL/min).
Hepatic impairment: In a similar study involving subjects with varying degrees of hepatic function, the mean AUC values of the volunteers with moderate hepatic impairment (Child-Pugh B) was 37% higher than in normal subjects, but still within the range seen in subjects without impaired function. In a study comparing the pharmacokinetics of Letrozole after a single oral dose in eight male subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh C) to those in healthy volunteers (N=8), AUC and t_1/2 increased by 95 and 187%, respectively. Thus, Letrozole should be administered with caution to patients with severe hepatic impairment and after consideration of the risk/benefit in the individual patient.