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Aromasin (Exemestane) - Description and Clinical Pharmacology

 
 



AROMASIN®
exemestane tablets

DESCRIPTION

AROMASIN® Tablets for oral administration contain 25 mg of exemestane, an irreversible, steroidal aromatase inactivator. Exemestane is chemically described as 6-methylenandrosta-1,4-diene-3,17-dione. Its molecular formula is C20H24O2 and its structural formula is as follows:

The active ingredient is a white to slightly yellow crystalline powder with a molecular weight of 296.41. Exemestane is freely soluble in N, N-dimethylformamide, soluble in methanol, and practically insoluble in water.

Each AROMASIN Tablet contains the following inactive ingredients: mannitol, crospovidone, polysorbate 80, hypromellose, colloidal silicon dioxide, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, simethicone, polyethylene glycol 6000, sucrose, magnesium carbonate, titanium dioxide, methylparaben, and polyvinyl alcohol.

CLINICAL PHARMACOLOGY

Mechanism of Action

Breast cancer cell growth may be estrogen-dependent. Aromatase is the principal enzyme that converts androgens to estrogens both in pre- and postmenopausal women. While the main source of estrogen (primarily estradiol) is the ovary in premenopausal women, the principal source of circulating estrogens in postmenopausal women is from conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by the aromatase enzyme in peripheral tissues. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer.

Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation, an effect also known as "suicide inhibition." Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme.

Pharmacokinetics

Following oral administration to healthy postmenopausal women, exemestane is rapidly absorbed. After maximum plasma concentration is reached, levels decline polyexponentially with a mean terminal half-life of about 24 hours. Exemestane is extensively distributed and is cleared from the systemic circulation primarily by metabolism. The pharmacokinetics of exemestane are dose proportional after single (10 to 200 mg) or repeated oral doses (0.5 to 50 mg). Following repeated daily doses of exemestane 25 mg, plasma concentrations of unchanged drug are similar to levels measured after a single dose.

Pharmacokinetic parameters in postmenopausal women with advanced breast cancer following single or repeated doses have been compared with those in healthy, postmenopausal women. Exemestane appeared to be more rapidly absorbed in the women with breast cancer than in the healthy women, with a mean tmax of 1.2 hours in the women with breast cancer and 2.9 hours in the healthy women. After repeated dosing, the average oral clearance in women with advanced breast cancer was 45% lower than the oral clearance in healthy postmenopausal women, with corresponding higher systemic exposure. Mean AUC values following repeated doses in women with breast cancer (75.4 ng∙h/mL) were about twice those in healthy women (41.4 ng∙h/mL).

Absorption

Following oral administration of radiolabeled exemestane, at least 42% of radioactivity was absorbed from the gastrointestinal tract. Exemestane plasma levels increased by approximately 40% after a high-fat breakfast.

Distribution

Exemestane is distributed extensively into tissues. Exemestane is 90% bound to plasma proteins and the fraction bound is independent of the total concentration. Albumin and α1-acid glycoprotein both contribute to the binding. The distribution of exemestane and its metabolites into blood cells is negligible.

Metabolism and Excretion

Following administration of radiolabeled exemestane to healthy postmenopausal women, the cumulative amounts of radioactivity excreted in urine and feces were similar (42 ± 3% in urine and 42 ± 6% in feces over a 1-week collection period). The amount of drug excreted unchanged in urine was less than 1% of the dose. Exemestane is extensively metabolized, with levels of the unchanged drug in plasma accounting for less than 10% of the total radioactivity. The initial steps in the metabolism of exemestane are oxidation of the methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many secondary metabolites. Each metabolite accounts only for a limited amount of drug-related material. The metabolites are inactive or inhibit aromatase with decreased potency compared with the parent drug. One metabolite may have androgenic activity (see Pharmacodynamics, Other Endocrine Effects). Studies using human liver preparations indicate that cytochrome P-450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane.

Special Populations

Geriatric

Healthy postmenopausal women aged 43 to 68 years were studied in the pharmacokinetic trials. Age-related alterations in exemestane pharmacokinetics were not seen over this age range.

Gender

The pharmacokinetics of exemestane following administration of a single, 25-mg tablet to fasted healthy males (mean age 32 years) were similar to the pharmacokinetics of exemestane in fasted healthy postmenopausal women (mean age 55 years).

Race

The influence of race on exemestane pharmacokinetics has not been evaluated.

Hepatic Insufficiency

The pharmacokinetics of exemestane have been investigated in subjects with moderate or severe hepatic insufficiency (Childs-Pugh B or C). Following a single 25-mg oral dose, the AUC of exemestane was approximately 3 times higher than that observed in healthy volunteers (see PRECAUTIONS).

Renal Insufficiency

The AUC of exemestane after a single 25-mg dose was approximately 3 times higher in subjects with moderate or severe renal insufficiency (creatinine clearance <35 mL/min/1.73 m2) compared with the AUC in healthy volunteers (see PRECAUTIONS).

Pediatric

The pharmacokinetics of exemestane have not been studied in pediatric patients.

Drug-Drug Interactions

Exemestane is metabolized by cytochrome P-450 3A4 (CYP 3A4) and aldoketoreductases. It does not inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 2D6, 2E1, and 3A4. In a clinical pharmacokinetic study, ketoconazole showed no significant influence on the pharmacokinetics of exemestane. Although no other formal drug-drug interaction studies have been conducted, significant effects on exemestane clearance by CYP isoenzymes inhibitors appear unlikely. In a pharmacokinetic interaction study of 10 healthy postmenopausal volunteers pretreated with potent CYP 3A4 inducer rifampicin 600 mg daily for 14 days followed by a single dose of exemestane 25 mg, the mean plasma Cmax and AUC 0–∞ of exemestane were decreased by 41% and 54%, respectively (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Pharmacodynamics

Effect on Estrogens

Multiple doses of exemestane ranging from 0.5 to 600 mg/day were administered to postmenopausal women with advanced breast cancer. Plasma estrogen (estradiol, estrone, and estrone sulfate) suppression was seen starting at a 5-mg daily dose of exemestane, with a maximum suppression of at least 85% to 95% achieved at a 25-mg dose. Exemestane 25 mg daily reduced whole body aromatization (as measured by injecting radiolabeled androstenedione) by 98% in postmenopausal women with breast cancer. After a single dose of exemestane 25 mg, the maximal suppression of circulating estrogens occurred 2 to 3 days after dosing and persisted for 4 to 5 days.

Effect on Corticosteroids

In multiple-dose trials of doses up to 200 mg daily, exemestane selectivity was assessed by examining its effect on adrenal steroids. Exemestane did not affect cortisol or aldosterone secretion at baseline or in response to ACTH at any dose. Thus, no glucocorticoid or mineralocorticoid replacement therapy is necessary with exemestane treatment.

Other Endocrine Effects

Exemestane does not bind significantly to steroidal receptors, except for a slight affinity for the androgen receptor (0.28% relative to dihydrotestosterone). The binding affinity of its 17-dihydrometabolite for the androgen receptor, however, is 100-times that of the parent compound. Daily doses of exemestane up to 25 mg had no significant effect on circulating levels of androstenedione, dehydroepiandrosterone sulfate, or 17-hydroxyprogesterone, and were associated with small decreases in circulating levels of testosterone. Increases in testosterone and androstenedione levels have been observed at daily doses of 200 mg or more. A dose-dependent decrease in sex hormone binding globulin (SHBG) has been observed with daily exemestane doses of 2.5 mg or higher. Slight, nondose-dependent increases in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels have been observed even at low doses as a consequence of feedback at the pituitary level. Exemestane 25 mg daily had no significant effect on thyroid function [free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH)].

Coagulation and Lipid Effects

In study 027 of postmenopausal women with early breast cancer treated with exemestane (N=73) or placebo (N=73), there was no change in the coagulation parameters activated partial thromboplastin time [APTT], prothrombin time [PT] and fibrinogen. Plasma HDL cholesterol was decreased 6–9% in exemestane treated patients; total cholesterol, LDL cholesterol, triglycerides, apolipoprotein-A1, apolipoprotein-B, and lipoprotein-a were unchanged. An 18% increase in homocysteine levels was also observed in exemestane treated patients compared with a 12% increase seen with placebo.

CLINICAL STUDIES

Adjuvant Treatment in Early Breast Cancer

The Intergroup Exemestane Study 031 (IES) was a randomized, double-blind, multicenter, multinational study comparing exemestane (25 mg/day) versus tamoxifen (20 or 30 mg/day) in postmenopausal women with early breast cancer. Patients who remained disease-free after receiving adjuvant tamoxifen therapy for 2 to 3 years were randomized to receive 3 to 2 years of AROMASIN or tamoxifen to complete a total of 5 years of hormonal therapy.

The primary objective of the study was to determine whether, in terms of disease-free survival, it was more effective to switch to AROMASIN rather than continuing tamoxifen therapy for the remainder of five years. Disease-free survival was defined as the time from randomization to time of local or distant recurrence of breast cancer, contralateral invasive breast cancer, or death from any cause.

The secondary objectives were to compare the two regimens in terms of overall survival and long-term tolerability. Time to contralateral invasive breast cancer and distant recurrence-free survival were also evaluated.

A total of 4724 patients in the intent-to-treat (ITT) analysis were randomized to AROMASIN (exemestane tablets) 25 mg once daily (N = 2352) or to continue to receive tamoxifen once daily at the same dose received before randomization (N = 2372). Demographics and baseline tumor characteristics are presented in Table 1. Prior breast cancer therapy is summarized in Table 2.

Table 1. Demographic and Baseline Tumor Characteristics from the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population)
ParameterExemestane
(N = 2352)
Tamoxifen
(N = 2372)
Age (years):
Median age (range)63.0 (38.0 – 96.0)63.0 (31.0 – 90.0)
Race, n (%):
Caucasian2315(98.4)2333(98.4)
Hispanic13  (0.6)13  (0.5)
Asian10  (0.4)9  (0.4)
Black7  (0.3)10  (0.4)
Other/not reported7  (0.3)7  (0.3)
Nodal status, n (%):
Negative1217(51.7)1228(51.8)
Positive1051(44.7)1044(44.0)
  1–3 Positive nodes721(30.7)708(29.8)
  4–9 Positive nodes239(10.2)244(10.3)
  >9 Positive nodes88  (3.7)86  (3.6)
  Not reported3  (0.1)6  (0.3)
Unknown or missing84  (3.6)100  (4.2)
Histologic type, n (%):
Infiltrating ductal1777(75.6)1830(77.2)
Infiltrating lobular341(14.5)321(13.5)
Other231  (9.8)213  (9.0)
Unknown or missing3  (0.1)8  (0.3)
Receptor status Results for receptor status include the results of the post-randomization testing of specimens from subjects for whom receptor status was unknown at randomization. , n (%):
ER and PgR Positive1331(56.6)1319(55.6)
ER Positive and PgR Negative/Unknown677(28.8)692(29.2)
ER Unknown and PgR Positive Only one subject in the exemestane group had unknown ER status and positive PgR status. /Unknown288(12.2)291(12.3)
ER Negative and PgR Positive6  (0.3)7  (0.3)
ER Negative and PgR Negative/Unknown (none positive)48  (2.0)58  (2.4)
Missing2  (0.1)5  (0.2)
Tumor Size, n (%):
≤ 0.5 cm58  (2.5)46  (1.9)
> 0.5 – 1.0 cm315(13.4)302(12.7)
> 1.0 – 2 cm 1031(43.8)1033(43.5)
> 2.0 – 5.0 cm833(35.4) 883(37.2)
> 5.0 cm62  (2.6)59  (2.5)
Not reported53  (2.3)49  (2.1)
Tumor Grade, n (%):
G1397(16.9)393(16.6)
G2977(41.5)1007(42.5)
G3454(19.3)428(18.0)
G423  (1.0)19  (0.8)
Unknown/Not Assessed/Not reported501(21.3)525(22.1)
Table 2. Prior Breast Cancer Therapy of Patients in the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population)
ParameterExemestane
(N = 2352)
Tamoxifen
(N = 2372)
Type of surgery, n (%):
Mastectomy1232(52.4)1242(52.4)
Breast-conserving1116(47.4)1123(47.3)
Unknown or missing4  (0.2)7  (0.3)
Radiotherapy to the breast, n (%):
Yes1524(64.8)1523(64.2)
No824(35.5)843(35.5)
Not reported4  (0.2)6  (0.3)
Prior therapy, n (%):
Chemotherapy774(32.9)769(32.4)
Hormone replacement therapy 567(24.1)561(23.7)
Bisphosphonates43  (1.8)34  (1.4)
Duration of tamoxifen therapy at randomization (months):
Median (range)28.5 (15.8 – 52.2)28.4 (15.6 – 63.0)
Tamoxifen dose, n (%):
20 mg2270(96.5)2287(96.4)
30 mg The 30 mg dose was used only in Denmark, where this dose was the standard of care. 78  (3.3)75  (3.2)
Not reported4  (0.2)10  (0.4)

After a median duration of therapy of 27 months and with a median follow-up of 34.5 months, 520 events were reported, 213 in the AROMASIN group and 307 in the tamoxifen group (Table 3).

Table 3. Primary Endpoint Events (ITT Population)
EventFirst Events
N (%)
Exemestane
(N = 2352)
Tamoxifen
(N = 2372)
Loco-regional recurrence34(1.45)45(1.90)
Distant recurrence126(5.36)183(7.72)
Second primary – contralateral breast cancer7(0.30)25(1.05)
Death – breast cancer1(0.04)6(0.25)
Death – other reason41(1.74)43(1.81)
Death – missing/unknown3(0.13)5(0.21)
Ipsilateral breast cancer1(0.04)0
Total number of events 213 (9.06) 307 (12.94)

Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.69, 95% CI: 0.58, 0.82, P = 0.00003, Table 4, Figure 1] in the AROMASIN arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 85% of the trial patients, disease-free survival was also statistically significantly improved (HR = 0.65, 95% CI: 0.53, 0.79, P = 0.00001) in the AROMASIN arm compared to the tamoxifen arm. Consistent results were observed in the subgroups of patients with node negative or positive disease, and patients who had or had not received prior chemotherapy. Overall survival was not significantly different in the two groups, with 116 deaths occurring in the AROMASIN group and 137 in the tamoxifen group.

Table 4. Efficacy Results from the IES Study in Postmenopausal Women with Early Breast Cancer
ITT Population Hazard Ratio
(95% CI)
p-value
(log-rank test)
Disease free survival 0.69 (0.58–0.82)0.00003
Time to contralateral breast cancer0.32 (0.15–0.72)0.00340
Distant recurrence free survival0.74 (0.62–0.90)0.00207
Overall survival 0.86 (0.67–1.10)0.22962
ER and/or PgR positive
Disease free survival 0.65 (0.53–0.79)0.00001
Time to contralateral breast cancer0.22 (0.08–0.57)0.00069
Distant recurrence free survival0.73 (0.59–0.90)0.00367
Overall survival 0.88 (0.67–1.17)0.37460
Figure 1. Disease Free Survival in the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population)

Treatment of Advanced Breast Cancer

Exemestane 25 mg administered once daily was evaluated in a randomized double-blind, multicenter, multinational comparative study and in two multicenter single-arm studies of postmenopausal women with advanced breast cancer who had disease progression after treatment with tamoxifen for metastatic disease or as adjuvant therapy. Some patients also have received prior cytotoxic therapy, either as adjuvant treatment or for metastatic disease.

The primary purpose of the three studies was evaluation of objective response rate (complete response [CR] and partial response [PR]). Time to tumor progression and overall survival were also assessed in the comparative trial. Response rates were assessed based on World Health Organization (WHO) criteria, and in the comparative study, were submitted to an external review committee that was blinded to patient treatment. In the comparative study, 769 patients were randomized to receive AROMASIN (exemestane tablets) 25 mg once daily (N = 366) or megestrol acetate 40 mg four times daily (N = 403). Demographics and baseline characteristics are presented in Table 5.

Table 5. Demographics and Baseline Characteristics from the Comparative Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Tamoxifen Therapy
ParameterAROMASIN
(N = 366)
Megestrol Acetate
(N = 403)
Median Age (range)65 (35–89)65 (30–91)
ECOG Performance Status
  0167 (46%)187 (46%)
  1162 (44%)172 (43%)
  234 (9%)42 (10%)
Receptor Status
  ER and/or PgR +246 (67%)274 (68%)
  ER and PgR unknown116 (32%)128 (32%)
    Responders to prior tamoxifen68 (19%)85 (21%)
    NE for response to prior tamoxifen46 (13%)41 (10%)
Site of Metastasis
  Visceral ± other sites207 (57%)239 (59%)
  Bone only61 (17%)73 (18%)
  Soft tissue only54 (15%)51 (13%)
  Bone & soft tissue43 (12%)38 (9%)
Measurable Disease287 (78%)314 (78%)
Prior Tamoxifen Therapy
  Adjuvant or Neoadjuvant145 (40%)152 (38%)
  Advanced Disease, Outcome
    CR, PR or SD≥ 6 months179 (49%)210 (52%)
    SD< 6 months, PD or NE42 (12%)41 (10%)
Prior Chemotherapy
  For advanced disease ± adjuvant58 (16%)67 (17%)
  Adjuvant only104 (28%)108 (27%)
  No chemotherapy203 (56%)226 (56%)

The efficacy results from the comparative study are shown in Table 6. The objective response rates observed in the two treatment arms showed that AROMASIN was not different from megestrol acetate. Response rates for AROMASIN from the two single-arm trials were 23.4% and 28.1%.

Table 6. Efficacy Results from the Comparative Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Tamoxifen Therapy
Response CharacteristicsAROMASIN
(N=366)
Megestrol Acetate
(N=403)
Abbreviations: CR = complete response, PR = partial response, SD = stable disease (no change), TTP = time to tumor progression, C.I. = confidence interval, MA = megestrol acetate, AR = AROMASIN
Objective Response Rate = CR + PR (%)15.012.4
                  Difference in Response Rate (AR-MA)2.6
                  95% C. I.7.5, -2.3
CR (%)2.21.2
PR (%)12.811.2
  SD ≥ 24 Weeks (%)21.321.1
Median Duration of Response (weeks)76.171.0
Median TTP (weeks)20.316.6
                  Hazard Ratio (AR-MA)0.84

There were too few deaths occurring across treatment groups to draw conclusions on overall survival differences. The Kaplan-Meier curve for time to tumor progression in the comparative study is shown in Figure 2.

Figure 2. Time to Tumor Progression in the Comparative Study of Postmenopausal Women With Advanced Breast Cancer Whose Disease Had Progressed After Tamoxifen Therapy

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