Pharmacology: Mechanism of Action: The growth of some cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (i.e., estrogen and/or progesterone receptor positive or receptor unknown) has included a variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational agents). These interventions lead to decreased tumor mass or delayed progression of tumor growth in some women.
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 in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.
Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum Luteinizing Hormone (LH), and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum Follicle Stimulating Hormone (FSH). Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.
Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticoid synthesis, aldosterone synthesis, or synthesis of thyroid hormones.
Pharmacodynamics: In postmenopausal patients with advanced breast cancer, daily doses of 100 mcg to 5 mg Letrozole suppress plasma concentrations of estradiol, estrone, and estrone sulfate by 75%-95% from baseline with maximal suppression achieved within two-three days. Suppression is dose-related, with doses of 500 mcg and higher giving many values of estrone and estrone sulfate that were below the limit of detection in the assays. Estrogen suppression was maintained throughout treatment in all patients treated at 500 mcg or higher. Letrozole is highly specific in inhibiting aromatase activity. There is no impairment of adrenal steroidogenesis. No clinically-relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, Adrenocorticotropic Hormone (ACTH) or in plasma renin activity among postmenopausal patients treated with a daily dose of Letrozole 100 mcg to 5 mg. The Adrenocorticotropic Hormone (ACTH) stimulation test performed after 6 and 12 weeks of treatment with daily doses of 100 mcg, 250 mcg, 500 mcg, 1 mg, 2.5 mg and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Glucocorticoid or mineralocorticoid supplementation is, therefore, not necessary. No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 100 mcg, 500 mcg and 2.5 mg single doses of Letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 100 mcg to 5 mg. This indicates that the blockade of estrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by Thyroid-Stimulating Hormone (TSH) levels, T3 uptake, and T4 levels.
Pharmacokinetics: Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is not affected by food. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway. About 90% of radiolabeled letrozole is recovered in urine. Letrozole's terminal elimination half-life is about 2 days and steady-state plasma concentration after daily 2.5 mg dosing is reached in 2-6 weeks. Plasma concentrations at steady-state are 1.5 to 2 times higher than predicted from the concentrations measured after a single dose, indicating slight non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. These steady-state levels are maintained over extended periods, however, and continuous accumulation of letrozole does not occur. Letrozole is weakly protein bound and has a large volume of distribution (approximately 1.9 L/kg).
Metabolism and Excretion: Metabolism to a pharmacologically-inactive carbinol metabolite (4, 4'-methanol bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of of letrozole clearance. Of the radiolabel recovered in urine, at least 75% was the glucuronide of the carbinol metabolite, about 9% was two unidentified metabolites, and 6% was unchangeable letrozole. In human microsomes with specific Cytochrome P450 (CYP) isozyme activity, CYP 3A4 metabolized letrozole to the carbinol metabolite while CYP 2A6 formed both this metabolite and its ketone analog. In human liver microsomes, letrozole strongly inhibited CYP 2A6 and moderately inhibited CYP 2C19.
Special Populations: Pediatric, Geriatric and Race: In the study populations (adults ranging in age from 35 to >80 years), no change in pharmacokinetic parameters was observed with increasing age. Differences in letrozole pharmacokinetics between adult and pediatric populations have not been studied. Differences in letrozole pharmacokinetics due to race have not been studied.
Renal Insufficiency: In a study of volunteers with varying renal function (24-hour creatinine clearance: 9-116 mL/min), no effect of renal function on the pharmacokinetics of single doses of 2.5 mg of letrozole tablets was found. In addition, in a study of 347 patients with advanced breast cancer, about half of whom received 2.5 mg Letrozole and half 500 mcg Letrozole, renal impairment (calculated creatinine clearance: 20-50 mL/min) did not affect steady-state plasma letrozole concentration.
Hepatic Insufficiency: In a study of subjects with varying degrees of non-metastatic hepatic dysfunction (e.g., cirrhosis, Child-Pugh classification A and B), the mean Area Under the Curve (AUC) values of the volunteers with moderate hepatic impairment were 37% higher than in normal subjects, but still within the range seen in subjects without impaired function. Patients with severe hepatic impairment (Child-Pugh classification C) have not been studied.