A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Faslodex Pharmacology, Pharmacokinetics, Studies, Metabolism - Fulvestrant
Faslodex Pharmacology, Pharmacokinetics, Studies, Metabolism - Fulvestrant
CLINICAL PHARMACOLOGY
Mechanism of Action
Many breast cancers have estrogen receptors (ER), and the growth
of these tumors can be stimulated by estrogen. Fulvestrant is an estrogen receptor
antagonist that binds to the estrogen receptor in a competitive manner with
affinity comparable to that of estradiol. Fulvestrant downregulates the ER protein
in human breast cancer cells.
In a clinical study in postmenopausal women with primary breast
cancer treated with single doses of FASLODEX 15-22 days prior to surgery, there
was evidence of increasing down regulation of ER with increasing dose. This
was associated with a dose-related decrease in the expression of the progesterone
receptor, an estrogen-regulated protein. These effects on the ER pathway were
also associated with a decrease in Ki67 labeling index, a marker of cell proliferation.
In vitro studies demonstrated that fulvestrant is a reversible
inhibitor of the growth of tamoxifen-resistant, as well as estrogen-sensitive
human breast cancer (MCF-7) cell lines. In in vivo tumor studies, fulvestrant
delayed the establishment of tumors from xenografts of human breast cancer MCF-7
cells in nude mice. Fulvestrant inhibited the growth of established MCF-7 xenografts
and of tamoxifen-resistant breast tumor xenografts. Fulvestrant resistant breast
tumor xenografts may also be cross-resistant to tamoxifen.
Fulvestrant showed no agonist-type effects in in vivo uterotropic
assays in immature or ovariectomized mice and rats. In in vivo studies in immature
rats and ovariectomized monkeys, fulvestrant blocked the uterotrophic action
of estradiol. In postmenopausal women, the absence of changes in plasma concentrations
of FSH and LH in response to fulvestrant treatment (250 mg monthly) suggests
no peripheral steroidal effects.
Pharmacokinetics
Following intravenous administration, fulvestrant is rapidly
cleared at a rate approximating hepatic blood flow (about 10.5 ml plasma/min/Kg).
After an intramuscular injection plasma concentrations are maximal at about
7 days and are maintained over a period of at least one month, with trough concentration
about one-third of Cmax. The apparent half-life was about 40 days. After administration
of 250 mg of fulvestrant intramuscularly every month, plasma levels approach
steady-state after 3 to 6 doses, with an average 2.5 fold increase in plasma
AUC compared to single dose AUC and trough levels about equal to the single
dose Cmax (see Table 1).
Table 1: Summary of fulvestrant pharmacokinetic parameters in
postmenopausal advanced breast cancer patients after intramuscular administration
of a 250 mg dose (Mean ± SD)
| |
Cmax ng/ml
|
Cmin ng/ml
|
AUC ng.d/ml
|
t½ days
|
CL ml/min
|
|
Single dose
|
8.5 ± 5.4
|
2.6 ± 1.1
|
131± 62
|
40 ± 11
|
690 ± 226
|
|
Multiple dose steady state
|
15.8 ± 2.4
|
7.4 ± 1.7
|
328 ± 48
|
|
|
Fulvestrant was subject to extensive and rapid distribution.
The apparent volume of distribution at steady state was approximately 3 to 5
L/kg. This suggests that distribution is largely extravascular. Fulvestrant
was highly (99%) bound to plasma proteins; VLDL, LDL and HDL lipoprotein fractions
appear to be the major binding components. The role of sex hormone-binding globulin,
if any, could not be determined.
Metabolism and Excretion:
Biotransformation and disposition of fulvestrant in humans
have been determined following intramuscular and intravenous administration
of 14C-labeled fulvestrant. Metabolism of fulvestrant appears to
involve combinations of a number of possible biotransformation pathways analogous
to those of endogenous steroids, including oxidation, aromatic hydroxylation,
conjugation with glucuronic acid and/or sulphate at the 2, 3 and 17 positions
of the steroid nucleus, and oxidation of the side chain sulphoxide. Identified
metabolites are either less active or exhibit similar activity to fulvestrant
in antiestrogen models. Studies using human liver preparations and recombinant
human enzymes indicate that cytochrome P-450 3A4 (CYP 3A4) is the only P-450
isoenzyme involved in the oxidation of fulvestrant; however, the relative contribution
of P-450 and non-P-450 routes in vivo is unknown.
Fulvestrant was rapidly cleared by the hepatobiliary route
with excretion primarily via the feces (approximately 90%). Renal elimination
was negligible (less than 1%).
Special Populations:
Geriatric-- In patients with breast cancer, there was no difference
in fulvestrant pharmacokinetic profile related to age (range 33 to 89 years).
Gender-- Following administration of a single intravenous dose,
there were no pharmacokinetic differences between men and women or between premenopausal
and postmenopausal women. Similarly, there were no apparent differences between
men and postmenopausal women after intramuscular administration.
Race-- In the advanced breast cancer treatment trials, the
potential for pharmacokinetic differences due to race have been evaluated in
294 women including 87.4% Caucasian, 7.8% Black, and 4.4% Hispanic. No differences
in fulvestrant plasma pharmacokinetics were observed among these groups. In
a separate trial, pharmacokinetic data from postmenopausal ethnic Japanese women
were similar to those obtained in non-Japanese patients.
Renal Impairment-- Negligible amounts of fulvestrant are eliminated
in urine; therefore, a study in patients with renal impairment was not conducted.
In the advanced breast cancer trials, fulvestrant concentrations in women with
estimated creatinine clearance as low as 30 mL/min were similar to women with
normal creatinine.
Hepatic Impairment-- Fulvestrant is metabolized primarily in
the liver. In clinical trials in patients with locally advanced or metastatic
breast cancer, pharmacokinetic data were obtained following administration of
a 250 mg dose of FASLODEX to 261 patients classified as having normal liver
function and to 24 patient with mild impairment. Mild impairment was defined
as an alanine aminotransferase concentration (at any visit) greater than the
upper limit of the normal (ULN) reference range, but less than 2 times the ULN;
or if any 2 of the following 3 parameters were between 1- and 2-times the ULN:
aspartate aminotransferase, alkaline phosphatase, or total bilirubin.
There was no clear relationship between fulvestrant clearance
and hepatic impairment and the safety profile in patients with mild hepatic
impairment was similar to that seen in patients with no hepatic impairment.
Safety and efficacy have not been evaluated in patients with moderate to severe
hepatic impairment (see PRECAUTIONS-Hepatic
Impairment and DOSAGE AND ADMINISTRATION-Hepatic
Impairment sections).
Pediatric--The pharmacokinetics of fulvestrant have not been
evaluated in pediatric patients.
Drug-Drug Interactions
There are no known drug-drug interactions. Fulvestrant does
not significantly inhibit any of the major CYP isoenzymes, including CYP 1A2,
2C9, 2C19, 2D6, and 3A4 in vitro, and studies of co-administration of fulvestrant
with midazolam indicate that therapeutic doses of fulvestrant have no inhibitory
effects on CYP 3A4 or alter blood levels of drug metabolized by that enzyme.
Also, although fulvestrant is partly metabolized by CYP 3A4, a clinical study
with rifampin, an inducer of CYP 3A4, showed no effect on the pharmacokinetics
of fulvestrant. Clinical studies of the effect of strong CYP 3A4 inhibitors
on the pharmacokinetics of fulvestrant have not been performed.
Clinical Studies
Efficacy of FASLODEX was established by comparison to the selective
aromatase inhibitor anastrozole in two randomized, controlled clinical trials
(one conducted in North America, the other in Europe) in postmenopausal women
with locally advanced or metastatic breast cancer. All patients had progressed
after previous therapy with an antiestrogen or progestin for breast cancer in
the adjuvant or advanced disease setting. The majority of patients in these
trials had ER+ and/or PgR+ tumors. Patients who had ER-/PgR- or unknown disease
must have shown prior response to endocrine therapy.
In both trials, eligible patients with measurable and/or evaluable
disease were randomized to receive either FASLODEX 250 mg intramuscularly once
a month (28 days + 3 days) or anastrozole 1 mg orally once a day. All patients
were assessed monthly for the first three months and every three months thereafter.
The North American trial was a double-blind, randomized trial in 400 postmenopausal
women. The European trial was an open, randomized trial conducted in 451 patients.
Patients on the FASLODEX arm of the North American trial received two separate
injections (2 X 2.5 ml), whereas FASLODEX patients received a single injection
(1 X 5 ml) in the European trial. In both trials, patients were initially randomized
to a 125 mg per month dose as well, but interim analysis showed a very low response
rate and low dose groups were dropped.
The effectiveness endpoints were response rates (RR), based
on the Union Internationale Contre le Cancer (UICC) criteria, and time to progression
(TTP). Survival time was also determined. Confidence intervals (95.4%) were
calculated for the difference in RR between the FASLODEX and anastrozole groups.
The hazard ratio for an unfavorable event, (such as disease progression or death)
between FASLODEX and anastrozole groups was also determined.
Table 2 provides the demographics and baseline characteristics
of the postmenopausal women randomized to FASLODEX 250 mg or anastrozole 1 mg.
TABLE 2: STUDY POPULATION DEMOGRAPHICS
|
Parameter
|
North American Trial
|
European Trial
|
|
FASLODEX 250 mg
|
Anastrozole 1 mg
|
FASLODEX 250 mg
|
Anastrozole 1 mg
|
|
No. of Participants
|
206
|
194
|
222
|
229
|
|
Median Age (yrs)
|
64
|
61
|
64
|
65
|
|
Age Range (yrs)
|
33 - 89
|
36 - 94
|
35 - 86
|
33 – 89
|
|
Receptor Status # (%)
|
|
|
|
|
|
ER Positive
|
170 (83%)
|
156 (80%)
|
156 (70%)
|
173 (76%)
|
|
ER/PgR Positive
|
179 (87%)
|
169 (87%)
|
163 (73%)
|
183 (80%)
|
|
ER/PgR Unknown
|
13 (6%)
|
15 (8%)
|
51 (23%)
|
37 (16%)
|
|
Previous Therapy
|
|
|
|
|
|
Tamoxifen
|
196 (95%)
|
187 (96%)
|
215 (97%)
|
225 (98%)
|
|
Adjuvant antiestrogen only
|
94 (46%)
|
94 (48%)
|
95 (43%)
|
100 (44%)
|
|
Antiestrogen for advanced disease
|
110 (53%)
|
97 (50%)
|
126 (57%)
|
129 (56%)
|
|
+/- adjuvant use
|
|
|
|
|
|
Cytotoxic Chemotherapy
|
129 (63%)
|
122 (63%)
|
94 (42%)
|
98 (43%)
|
|
Site of Metastases
|
|
|
|
|
|
Visceral only *
|
39 (19%)
|
45 (23%)
|
30 (14%)
|
41 (18%)
|
|
Viscera
|
|
|
|
|
|
Liver involvement
|
47 (23%)
|
45 (23%)
|
48 (22%)
|
56 (24%)
|
|
Lung involvement
|
63 (31%)
|
60 (31%)
|
56 (25%)
|
60 (26%)
|
|
Bone only
|
47 (23%)
|
43 (22%)
|
38 (17%)
|
40 (17%)
|
|
Soft Tissue only
|
12 (6%)
|
13 (7%)
|
11 (5%)
|
8 (3%)
|
|
Skin and soft tissue
|
43 (21%)
|
41 (21%)
|
40 (18%)
|
35 (15%)
|
*Defined as liver or lung metastatic, or recurrent, disease
ER/PgR Positive defined as ER positive or PgR positive
ER/PgR Unknown defined as ER unknown and PgR unknown
Results of the trials, after a minimum follow-up duration of
14.6 months, are summarized in Table 3. The effectiveness of FASLODEX 250 mg
was determined by comparing RR and TTP results to anastrozole 1 mg, the active
control. With respect to response rate, the two studies ruled out (by one-sided
97.7% confidence limit) inferiority of FASLODEX to anastrozole of 6.3% and 1.4%.
Table 3: Efficacy Results
| |
North American Trial
|
European Trial
|
|
End point
|
FASLODEX 250 mg (n=206)
|
Anastrozole 1 mg (n=194)
|
FASLODEX 250 mg (n=222)
|
Anastrozole 1 mg (n=229)
|
|
|
|
Objective tumor response Number (%) of subjects with
CR + PR
|
35 (17.0)
|
33 (17.0)
|
45 (20.3)
|
34 (14.9)
|
|
|
| |
|
|
|
|
|
% Difference in Tumor Response Rate (FAS-ANA)
|
0.0
|
5.4
|
|
2-sided 95.4% CI
|
(-6.3, 8.9)
|
(-1.44, 14.8)
|
|
Stable Disease for ³
24
|
|
|
|
|
|
weeks (%)
|
26.7
|
19.1
|
24.3
|
30.1
|
|
Time to progression (TTP)
|
|
|
|
|
|
Median TTP (days)
|
165
|
103
|
166
|
156
|
|
Hazard ratio (FAS/ANA)
|
0.9
|
1.0
|
|
2-sided 95.4% CI
|
(0.7 to 1.1)
|
(0.8 to 1.26)
|
|
Survival Time
|
|
|
|
|
|
Died n (%)
|
109 (52.9%)
|
92 (47.4%)
|
125 (56.3%)
|
130 (56.8%)
|
|
Median Survival (days)
|
837
|
901
|
803
|
742
|
|
Hazard Ratio
|
1.1
|
1.0
|
|
2-sided 95% CI
|
(0.8, 1.5)
|
(0.8, 1.3)
|
CR = Complete Response; PR = Partial Response; CI = Confidence
Interval; FAS = FASLODEX; ANA = anastrozole
There are no efficacy data for the use of FASLODEX in premenopausal
women with advanced breast cancer (women with functioning ovaries as evidenced
by menstruation and/or premenopausal LH, FSH and estradiol levels).
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