Estrogen suppression in premenopausal women following 8 weeks of treatment with exemestane and triptorelin versus triptorelin alone.

INTRODUCTION: Luteinizing hormone-releasing hormone (LHRH) agonists (e.g., triptorelin) reduce ovarian estrogen production in premenopausal women with hormone-sensitive breast cancer. Aromatase inhibitors (e.g., exemestane) inhibit extraovarian production of estrogen and may further reduce circulating estrogens when combined with an LHRH agonist. METHODS: Healthy premenopausal women were randomized to receive 3.75 mg triptorelin (T) on days 1 and 29 with 25 mg exemestane (EX) or matched placebo once daily for 8 weeks, from day 1 to day 56. The primary objective was to evaluate the effect of T +/- EX on estradiol (E(2)) suppression by comparing the AUC(day 36-57 )for the 2 treatments. Secondary objectives included evaluation of estrone (E(1)), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) suppression; effects of EX on the T-induced gonadotrophin and estrogen flare; pharmacokinetics (PK); and safety. RESULTS: Twenty-eight (14 in each arm) were evaluable for efficacy and PK. Mean plasma estrogen levels (AUC(day 36-57)) were significantly lower for subjects who received T + EX than for subjects who received T alone (20.6 vs. 54.0 pg d/ml [-62%; P < 0.05], and 38.9 vs. 198.0 pg d/ml [-80%; P < 0.01] for E(2) and E(1), respectively). Coadministration of EX did not affect the initial flare or subsequent suppression of LH and FSH following the first dose of T, or the PK of T. Both treatments were well tolerated. CONCLUSIONS: Coadministration of T and EX resulted in greater estrogen suppression than when T was given alone. These findings could translate into improved clinical outcomes for premenopausal breast cancer patients receiving LHRH agonists.

Aromatase inhibitors: are there differences between steroidal and nonsteroidal aromatase inhibitors and do they matter?

Aromatase inhibitors (AIs) are approved for use in both early- and advanced-stage breast cancer in postmenopausal women. Although the currently approved "third-generation" AIs all powerfully inhibit estrogen synthesis, they may be subdivided into steroidal and nonsteroidal inhibitors, which interact with the aromatase enzyme differently. Nonsteroidal AIs bind noncovalently and reversibly to the aromatase protein, whereas steroidal AIs may bind covalently and irreversibly to the aromatase enzyme. The steroidal AI exemestane may exert androgenic effects, but the clinical relevance of this has yet to be determined. Switching between steroidal and nonsteroidal AIs produces modest additional clinical benefits, suggesting partial noncrossresistance between the classes of inhibitor. In these circumstances, the response rates to the second AI have generally been low; additional research is needed regarding the optimal sequence of AIs. To date, clinical studies suggest that combining an estrogen-receptor blocker with a nonsteroidal AI does not improve efficacy, while combination with a steroidal AI has not been evaluated. Results from head-to-head trials comparing steroidal and nonsteroidal AIs will determine whether meaningful clinical differences in efficacy or adverse events exist between the classes of AI. This review summarizes the available evidence regarding known differences and evaluates their potential clinical impact.

The effect of tamoxifen or exemestane on bone mineral density during the first 2 years of adjuvant treatment of postmenopausal women with early breast cancer.

BACKGROUND: Adjuvant therapy with aromatase inhibitors is associated with increased bone loss in postmenopausal women with breast cancer. We assessed changes in bone mineral density (BMD) from baseline to 24 months in patients receiving either tamoxifen (T) or exemestane (E). PATIENTS AND METHODS: A total of 578 women randomly assigned to T 20 mg per day orally or E 25 mg/day orally enrolled in this substudy; baseline, 12-month, and 24-month BMD measurements of the femur and lumbar spine by dual-energy x-ray absorptiometry were planned. Women receiving bone antiresorptive agents were excluded. Mean BMD changes from baseline to 12 and 24 months were tested between the treatment groups using 2-sample t tests and both g/cm2 (as percent changes) and T scores (as differences from baseline). RESULTS: A total of 167 women with all 3 imaging studies were evaluable and form the basis of this report (T=89, E=78). Using T scores, the mean difference from baseline was significant between the 2 groups at 12 months at both the spine (P=.0002) and the hip (P=.0004), and at 24 months only at the hip (P=.02). CONCLUSION: More bone loss occurred during the first 12 months of treatment with E compared with T, but by 2 years the differences were less apparent and bone loss with E had slowed.

Synthesis of exemestane labelled with (13)C.

The synthesis of exemestane Aromasin, an irreversible steroidal aromatase inhibitor, specifically labelled with (13)C is reported. The preparation of [(13)C(3)]exemestane was achieved according to an eight-step procedure starting from the commercially available testosterone.

Pharmacokinetics and dose finding of a potent aromatase inhibitor, aromasin (exemestane), in young males.

Suppression of estrogen, via estrogen receptor or aromatase blockade, is being investigated in the treatment of different conditions. Exemestane (Aromasin) is a potent and selective irreversible aromatase inhibitor. To characterize its suppression of estrogen and its pharmacokinetic (PK) properties in males, healthy eugonadal subjects (14-26 yr of age) were recruited. In a cross-over study, 12 were randomly assigned to 25 and 50 mg exemestane daily, orally, for 10 d with a 14-d washout period. Blood was withdrawn before and 24 h after the last dose of each treatment period. A PK study was performed (n = 10) using a 25-mg dose. Exemestane suppressed plasma estradiol comparably with either dose [25 mg, 38% (P

A predictive model for exemestane pharmacokinetics/pharmacodynamics incorporating the effect of food and formulation.

AIMS: Exemestane (Aromasin) is an irreversible aromatase inactivator used for the treatment of postmenopausal women with advanced breast cancer. The objective of this study was to evaluate the effect of formulation comparing a sugar-coated tablet (SCT) with a suspension and food on the pharmacokinetics (PK) and pharmacodynamics (PD) with respect to plasma estrone sulphate (E1S) concentrations of exemestane, using a PK/PD approach. METHODS: This was an open, three-period, randomized, crossover study. Twelve healthy postmenopausal women received single oral doses of 25 mg exemestane as a SCT after fasting or food and as a suspension after fasting. Exemestane and E1S concentrations were determined before and up to 14 days after drug administration. Population analysis was performed in two steps: (i) a compartmental PK model was selected incorporating the effect of food and formulation; (ii) conditional on the PK model, a PD model was developed employing indirect response models. Model selection was performed using standard statistical tests. Validation and assessment of the predictive capability of the selected model was performed using real test data sets obtained from the literature. RESULTS: A three-compartment model with first-order elimination rate best described exemestane disposition (k12 0.454, k21 0.158, k13 0.174, k31 0.016 and k 0.738 h(-1)). Absorption was described by a mono-exponential function [ka 2.3 (SCT after fasting), 1.1 (SCT after food) and 7.6 h(-1) (suspension); lag time 0.2 h]. The PD model assumed that E1S plasma concentrations are determined by a zero-order synthesis rate (6.5 pg ml(-1) h(-1)) and a first-order elimination constant (0.032 h(-1)). Exemestane inhibited E1S synthesis with a C50 value of 22.1 pg ml(-1). The mean population estimates were used to simulate the administration of different doses of the drug (0.5, 1, 2.5, 5 and 25 mg day(-1)). The model predictions were in agreement with historical data. CONCLUSIONS: Exemestane absorption is influenced by the formulation of the drug and by food, but its disposition is independent of both. PK differences do no translate into clinically important differences in the PD. The PK/PD model developed was able to predict successfully the response to different doses and administration schedules with respect to oestrogen suppression.