DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1762 administered once daily for 28 days, reduces total body androgen aromatization
by 96.7% or 98.1%, respectively. In addition, anastrozole
reduces aromatization in large, ER + breast tumors.
Absorption, Fate, and Excretion. Anastrozole is absorbed rapidly
after oral administration, reaching maximal plasma concentrations
after 2 hours. Repeated dosing increases plasma concentrations of
anastrozole, and steady-state is attained after 7 days. Although a
high-fat breakfast slows absorption, the meal does not significantly
alter the ultimate steady-state concentration achieved with multiple
dosing. Anastrozole is metabolized by N-dealkylation, hydroxylation,
and glucuronidation. The main metabolite of anastrozole is a
triazole. In addition, several other metabolites with no pharmacological
activity are formed. Less than 10% of the drug is excreted as
the unmetabolized parent compound. The principal excretory pathway
is via the liver and biliary tract. The elimination t 1/2
is ~50 hours.
The pharmacokinetics of anastrozole, which can be affected by drug
interactions via the CYP system, are not altered by co-administration
of tamoxifen or cimetidine (Köberle and Thürlimann, 2001).
Therapeutic Uses. Anastrozole (ARIMIDEX), 1 mg administered orally
once daily, is approved for upfront adjuvant hormonal therapy in
postmenopausal women with early-stage breast cancer and as
treatment for advanced breast cancer. In early-stage breast cancer,
anastrozole is significantly more effective than tamoxifen in delaying
time to tumor recurrence and decreasing the odds of a primary
contralateral tumor (Baum et al., 2002). In advanced breast cancer,
the results of two large, randomized trials in postmenopausal women
with disease progression while taking tamoxifen showed a statistically
significant survival advantage with anastrozole 1 mg/day versus
megestrol acetate 40 mg four times daily. In another phase III
clinical trial on women with ER + or PR + metastatic breast cancer,
anastrozole showed a statistically significant advantage over tamoxifen
in median time to disease progression (Bonneterre et al., 2001).
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Adverse Effects and Toxicity. Compared to tamoxifen, anastrozole has
been associated with a significantly lower incidence of vaginal bleeding,
vaginal discharge, hot flashes, endometrial cancer, ischemic cerebrovascular
events, venous thromboembolic events, and deep venous
thrombosis, including pulmonary embolism. Anastrozole is associated
with a higher incidence of musculoskeletal disorders and fracture
than tamoxifen. In the advanced disease setting, anastrozole is as well
tolerated as megestrol and causes less weight gain. In addition, anastrozole
is as well tolerated as tamoxifen, with a low rate of withdrawal
due to drug-related adverse events (2%).
The estrogen depletion caused by anastrozole and other AIs
raises the concern of bone loss. Compared with tamoxifen, treatment
with anastrozole results in significantly lower BMD in the lumbar
spine and total hip (Eastell et al., 2008). Bisphosphonates prevent AIinduced
bone loss in postmenopausal women (Brufsky et al., 2007).
Anastrozole has no clinically significant effect on adrenal
glucocorticoid or mineralocorticoid synthesis in postmenopausal
women. Anastrozole also does not affect ACTH-stimulated release
of cortisol or aldosterone, plasma concentrations of FSH or LH in
postmenopausal women, or TSH levels.
Letrozole. Letrozole is approved for upfront adjuvant
hormonal therapy in postmenopausal women with
early-stage breast cancer and as treatment for advanced
breast cancer.
Actions. In postmenopausal women with primary breast cancer, letrozole
inhibits estrogen aromatization by 99% and reduces local aromatization
within the tumors. The drug has no significant effect on the
synthesis of adrenal steroids or thyroid hormone and does not alter
levels of a range of other hormones. Letrozole also reduces cellular
markers of proliferation to a significantly greater extent than tamoxifen
in human estrogen-dependent tumors that overexpress HER1
and HER2/neu.
Letrozole increases the levels of bone resorption markers in
healthy postmenopausal women and in those with a history of breast
disease but without current active disease. Letrozole has not demonstrated
a consistent effect on serum lipid levels in healthy women or
postmenopausal women with breast cancer.
Absorption, Fate, and Excretion. Letrozole is rapidly absorbed after
oral administration, and maximum plasma levels are reached ~1 hour
after ingestion. Letrozole has a bioavailability of 99.9%. Steady-state
plasma concentrations of letrozole are reached after 2-6 weeks of
treatment. Following metabolism by CYP2A6 and CYP3A4, letrozole
is eliminated as an inactive carbinol metabolite mainly via the
kidneys. The total body clearance is low (2.2 L/h); the elimination t 1/2
is ~41 hours.
Therapeutic Uses. The usual dose of letrozole (FEMARA) is 2.5 mg
administered orally once daily. In early-stage breast cancer, extending
adjuvant endocrine therapy with letrozole (beyond the standard
5-year period of tamoxifen) improves disease-free survival compared
with placebo and improves overall survival in the subset of patients
with positive axillary nodes (Goss et al., 2004). Furthermore, upfront
letrozole is significantly more effective than upfront tamoxifen in
terms of time to tumor recurrence and odds of a primary contralateral
tumor (Thürlimann et al., 2005).
In advanced breast cancer, letrozole is superior to tamoxifen
as first-line treatment; time to disease progression is significantly
longer and objective response rate is significantly greater with letrozole,
but median overall survival is similar between groups
(Mouridsen et al., 2003). As second-line therapy of advanced breast
cancer that has progressed on tamoxifen or after oophorectomy,
letrozole has efficacy equal to that of anastrozole and similar to or
better than that of megestrol.
Adverse Effects and Toxicity. Letrozole is well tolerated; the most common
treatment-related adverse events are hot flashes, nausea, and hair
thinning. In patients with tumors that progressed on anti-estrogen therapy,
letrozole was tolerated at least as well as, or better than, megestrol.
In the trial of extended adjuvant therapy, adverse events reported more
frequently with letrozole than placebo were hot flashes, arthralgia, myalgia,
and arthritis, but patients discontinued letrozole no more frequently
than placebo in this double-blind trial. Letrozole has a low overall incidence
of cardiovascular side effects (Mouridsen et al., 2007).
A greater number of new diagnoses of osteoporosis occurred
among women receiving letrozole. Compared with tamoxifen, the
use of upfront letrozole results in significantly more clinical fractures.
Bisphosphonates prevent letrozole-induced bone loss in postmenopausal
women (Brufsky et al., 2007).
Exemestane. Exemestane (AROMASIN) is a more potent,
orally administered analog of the natural aromatase
substrate, androstenedione, and lowers estrogen levels
more effectively than does its predecessor, formestane.