Pharmacology: Pharmacodynamics: Mechanism of action:
Exemestane is an irreversible, steroidal aromatase inhibitor, structurally related to the natural substrate androstenedione. In postmenopausal women, oestrogens are produced primarily form the conversion of androgens into oestrogens through the aromatase enzyme in peripheral tissues. Oestrogen deprivation through aromatase inhibition is an effective and selective treatment for hormone dependent breast cancer in postmenopausal women. In postmenopausal women, Exemestane p.o. significantly lowered serum oestrogen concentrations starting for a 5 mg dose, reaching maximal suppression (>90%) with a dose of 10-25 mg. In post menopausal breast cancer patients treated with the 25 mg daily dose, whole body aromatization was reduced by 98%.
Exemestane does not possess any progestogenic or oestrogenic activity. A slight androgenic activity, probably due to the 17-hydro derivative, has been observed mainly at high doses. In multiple daily dose trials, Exemestane had no detectable effects on adrenal biosynthesis of cortisol or aldosterone, measured before or after ACTH challenge, thus demonstrating its selectivity with regard to the other enzymes involved in the steroidogenic pathway. Glucocorticoid or mineralocorticoid replacements are therefore not needed. A non dose dependent slight increase in serum LH and FSH levels has been observed even at low doses: this effect is, however, expected for the pharmacological class and is probably the result of feedback at the pituitary level due to the reduction in oestrogen levels that stimulate the pituitary secretion of gonadotropins also in postmenopausal women.
Adjuvant Treatment of Early Breast Cancer:
In a multicentre, randomized, double-blind study, conducted in 4724 postmenopausal patients with oestrogen receptor positive or unknown primary breast cancer, patients who had remained disease free after receiving adjuvant tamoxifen therapy for 2 to 3 years were randomized to receive 3 to 2 years of Exemestane (25 mg/day) or tamoxifen (20 or 30 mg/day) to complete a total of 5 years of hormonal therapy.
After a median duration of therapy of about 30 months and a median follow-up of about 52 months, results showed that sequential treatment with Exemestane after 2 to 3 years of adjuvant tamoxifen therapy was associated with a clinically and statistically significant improvement in disease free survival (DFS) compared with continuation of tamoxifen therapy. Analysis showed that in the observed study period Exemestane reduced the risk of breast cancer recurrence by 24% compared with tamoxifen (hazard ratio 0.76; p=0.00015).
The beneficial effect of Exemestane over tamoxifen with respect to DFS was apparent regardless of nodal status or prior chemotherapy.
Exemestane also significantly reduced the risk of contralateral breast cancer (hazard ratio 0.57, p=0.04158).
In the whole study population, a trend for improved overall survival was observed for Exemestane (222 deaths) compared to tamoxifen (262 deaths) with a hazard ratio 0.85 (logrank test: p=0.07362), representing a 15% reduction in the risk of death in favor of Exemestane. A statistically significant 23% reduction in the risk of dying (hazard ratio for overall survival 0.77; Wald chi square test: p=0.0069) was observed for Exemestane compared to tamoxifen when adjusting for the prespecified prognostic factors (i.e., ER status, nodal status, prior chemotherapy, use of HRT and use of biphosphonates).
Main efficacy results in all patients (intention to treat population) and oestrogen receptor positive patients are summarised in the table as follows: See Table 1.
Click on icon to see table/diagram/image
In the additional analysis for the subset of patients with oestrogen receptor positive or unknown status, the unadjusted overall survival hazard ratio was 0.83 (log rank test: p=0.04250), representing a clinically and statistically significant 17% reduction in the risk of dying.
Results from a bone sub study demonstrated that women treated with Exemestane following 2 to 3 years of tamoxifen treatment experienced moderate reduction in bone mineral density. In the overall study, the treatment emergent fracture incidence evaluated during the 30 months treatment period was higher in patients treated with Exemestane compared with tamoxifen (4.5% and 3.3% correspondingly, p=0.038.
Results from a endometrial sub study indicate that after 2 years of treatment there was a median 33% reduction of endometrial thickness in the Exemestane treated patients compared with no notable variation in the tamoxifen treated patients. Endometrial thickening, reported at the start of study treatment, was reversed to normal (< 5 mm) for 54% of patients treated with Exemestane.
Treatment of Advanced Breast Cancer:
Exemestane is used in the treatment of advanced breast cancer in postmenopausal women disease has progressed following tamoxifen therapy. Efficacy was evaluated in one comparative study (versus megestrol acetate) and 2 single-arm studies in postmenopausal women with advanced breast cancer that progressed after tamoxifen therapy for metastatic disease or as adjuvant therapy; some patients also received prior chemotherapy either for metastasis or as adjuvant therapy. The studies evaluated objective response rates (complete and partial response); time to tumor progression (TTP) and overall survival also were assessed in the comparative study. In the comparative study, objective response rates for exemestane and megestrol were comparable at 15 and 12.4%, respectively. Response rates of exemestane in the 2 single-arm studies were 23.4 and 28.1%. In the comparative study, the median duration of response was 76.1 and 71 weeks for exemestane and megestrol, respectively, and the median TTP was 20.3 and 16.6 weeks, respectively. No conclusions could be drawn related to overall survival differences with the limited study data available.
After oral administration of Exemestane tablets. Exemestane is absorbed rapidly. The fraction of the dose absorbed from the gastrointestinal tract is high. The absolute bioavailability in humans is unknown, although it is anticipated to be limited by an extensive first pass effect. A similar effect resulted in an absolute bioavailability in rats and dogs of 5%. After a single dose of 25 mg, maximum plasma levels of 18 ng/ml are reached after 2 hours. Concomitant intake with food increases the bioavailability by 40%.
The volume of distribution of Exemestane, not corrected for the oral bioavailability, is ca 20000 l. The kinetics is linear and the terminal elimination half life is 24 h. Binding to plasma proteins is 90% and is concentration independent. Exemestane and its metabolites do not bind to red blood cells.
Exemestane does not accumulate in an unexpected way after repeated dosing.
Metabolism and excretion:
Exemestane is metabolised by oxidation of the methylene moiety on the 6 position by CYP 3A4 isoenzyme and/or reduction of the 17-keto group by aldoketoreductase followed by conjugation. The clearance of Exemestane is ca 500 l/h, not corrected for the oral bioavailability. The metabolites are inactive or the inhibition of aromatase is less than the parent compound.
The amount excreted unchanged in urine is 1% of the dose. In urine and faces equal amounts (40%) of 14C labeled Exemestane were eliminated within a week.
Age: No significant correlation between the systemic exposure of Exemestane and the age of subjects has been observed.
Renal insufficiency: In patients with severe renal impairment (CLcr < 30 ml/min) the systemic exposure to Exemestane was 2 times higher compared with healthy volunteers. Given the safety profile of Exemestane, no dose adjustment is considered to be necessary.
Hepatic insufficiency: In patients with moderate or severe hepatic impairment the exposure of Exemestane is 2-3 fold higher compare with healthy volunteers. Given the safety profile of Exemestane, no dose adjustment is considered to be necessary.