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

1760 Steady-state concentrations are reached after three to six monthly
injections. There is extensive and rapid distribution and extensive
protein binding of this highly lipophilic drug.
Various pathways, similar to those of steroid metabolism
(oxidation, aromatic hydroxylation, and conjugation), extensively
metabolize fulvestrant. CYP3A4 appears to be the only CYP
isoenzyme involved in the metabolism of fulvestrant. However,
several preclinical and clinical studies indicate that fulvestrant is
not subject to CYP3A4 interactions that might affect its pharmacokinetics,
safety, or efficacy; however, the effects of strong
CYP3A4 inhibitors have not been studied. The putative metabolites
possess no estrogenic activity, and only the 17-keto compound
demonstrates a level of anti-estrogenic activity, which is
~22% that of fulvestrant. Less than 1% of the parent drug is
excreted intact in the urine.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Dosing. The approved dosing for fulvestrant is 250 mg by intramuscular
injection monthly. Because pharmacokinetic data have shown
that it takes ~3-6 months for fulvestrant to reach steady-state levels
with monthly dosing, alternative regimens have been studied. A loading
dose regimen of 500 mg on day 0, 250 mg on days 14 and 28,
and then 250 mg each month (McCormack and Sapunar, 2008)
yields maximum fulvestrant concentrations in plasma an average of
12 days after the first dose and maintains those levels thereafter.
Therapeutic Uses. Fulvestrant is used in postmenopausal women as
anti-estrogen therapy of hormone receptor–positive metastatic breast
cancer after progression on first-line anti-estrogen therapy such as
tamoxifen (Strasser-Weippl and Goss, 2004). Fulvestrant is at least
as effective in this setting as the third-generation AI anastrozole.
Substrate
O
Fulvestrant 250 mg (administered as a once-monthly 5-mL
intramuscular injection) also has been compared with tamoxifen
20 mg (orally once daily) in a trial of postmenopausal women with
ER + and/or PR + or ER/PR-unknown metastatic breast cancer who
had not previously received endocrine or chemotherapy. In patients
with ER + and/or PR + disease, there was no difference between fulvestrant
and tamoxifen in time to disease progression or overall
response rate (Vergote and Robertson, 2004). The long time to
steady-state plasma levels for fulvestrant has brought into question
the results of studies that lacked a loading dose, and trials are in
progress to test the relative efficacy of giving an initial loading
dose followed by regular monthly injections.
Toxicity and Adverse Effects. Fulvestrant generally is well tolerated,
the most common adverse effects being nausea, asthenia, pain, vasodilation
(hot flashes), and headache. The risk of injection site reactions,
seen in ~7% of patients, is reduced by giving the injection slowly. In
the study comparing anastrozole and fulvestrant in tamoxifenresistant
patients, the drugs had equivalent quality-of-life outcome
measures (Vergote and Robertson, 2004).
AROMATASE INHIBITORS
Aromatase inhibitors (AIs; Figure 63–3) block the
function of the aromatase enzyme that converts androgens
to estrogens. AIs now are considered the standard
of care for adjuvant treatment of postmenopausal
women with hormone receptor–positive breast cancer,
either as initial therapy or sequenced after tamoxifen.
Type I Inhibitors
(steroidal inactivators)
O
O
O
O
O
ANDROSTENEDIONE
OH CH 2
FORMESTANE
EXEMESTANE
(second generation)
(third generation)
Type 2 Inhibitors
(non-steroidal inactivators)
N
N
N
NC
N
N
N
C 2 H 2
H 3 C CH3 H 3 C CH 3
NH 2
NC
CN
O
N
O
CN
AMINOGLUTETHIMIDE
(first generation)
ANASTROZOLE
(third generation)
Figure 63–3. Structure of the main aromatase inhibitors and the natural substrate androstenedione.
LETROZOLE
(third generation)