An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane

Abstract

BACKGROUND The newer generation, nonsteroidal aromatase inhibitors (AIs) anastrozole and letrozole have shown superior efficacy compared with tamoxifen as first‐line treatments and compared with megestrol acetate as second‐line therapy in postmenopausal women with advanced breast carcinoma. In an open‐label, Phase II trial, it was reported that exemestane showed numerical superiority compared with tamoxifen for objective response and clinical benefit. Because these agents ultimately may be administered for periods of up to 5 years in the adjuvant setting, it is of increasing importance to assess their tolerability and pharmacologic profiles. METHODS In the absence of data from direct clinical comparisons, the published literature was reviewed for the clinical pharmacology, pharmacokinetic characteristics, and selectivity profiles of anastrozole, letrozole, and exemestane. RESULTS At clinically administered doses, the plasma half‐lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) were 41–48 hours, 2–4 days, and 27 hours, respectively. The time to steady‐state plasma levels was 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have been reported only with exemestane. Anastrozole treatment had no impact on plasma lipid levels, whereas both letrozole and exemestane had an unfavorable effect on plasma lipid levels. In indirect comparisons, anastrozole showed the highest degree of selectivity compared with letrozole and exemestane in terms of a lack of effect on adrenosteroidogenesis. CONCLUSIONS All three AIs demonstrated clinical efficacy over preexisting treatments. However, there were differences in terms of pharmacokinetics and effects on lipid levels and adrenosteroidogenesis. The long‐term clinical significance of these differences remains to be elucidated. Cancer 2002;95:2006–16. © 2002 American Cancer Society. DOI 10.1002/cncr.10908

Discovery of novel aromatase inhibitors using a homogeneous time-resolved fluorescence assay

“…These AIs such as anastrozole and letrozole [41,42] , by non-covalently binding to the aromatase enzyme heme moiety and preventing androgen binding by saturating the binding site, are a successful alternative to tamoxifen as a first-line therapy in postmenopausal women. However, several clinical trials in postmenopausal breast cancer patients and healthy postmenopausal women treated with AIs evalu- A clinical trial that evaluated the effects of anastrozole, letrozole and exemestane on bone health demonstrated that after 24 weeks of treatment, all 3 inhibitors caused increased bone resorption and decreased bone formation [43] .…”

Treatment of testosterone-induced gynecomastia with the aromatase inhibitor, anastrozole

“…4 Other aromatase inhibitors, such as the first-generation aminoglutethimide, have limited use due to toxicity and lack of selectivity for the aromatase enzyme, necessitating concomitant corticosteroid supplementation in some cases. 5 In men, aromatase inhibitors have been used in the treatment of male infertility, in the hopes of achieving an improved testosterone-to-estradiol ratio. Raman and Schlegel 3 noted significant improvement in sperm concentration, motility and morphology in a group of men treated with anastrozole.…”

The use of aromatase inhibitors in boys with short stature: what to know before prescribing?

“…This fact is due to the probable nonlinear kinetics of letrozole. The half-life of anastrozole after a single 1-mg dose is 48 hours, while that of letrozole is 4 days or more after a 2.5-mg oral dose (19). At therapeutic doses, around 40% of the anastrozole is bound to plasma proteins (20), while this protein binding rate is around 60% for letrozole (21).…”