Pharmacokinetics and dose finding of a potent aromatase inhibitor, aromasin (exemestane), in young males.
Mauras N, Lima J, Patel D, Rini A, di Salle E, Kwok A, Lippe B.
Source
Nemours Children's Clinic and Research Programs, Jacksonville, Florida 32207, USA.
nmuras@nemours.org
Erratum in
J Clin Endocrinol Metab. 2004 Feb;89(2):732.
Abstract
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 Blood was withdrawn before and 24 h after the last dose of each treatment period.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 <or= 0.002); 50 mg, 32% (P <or= 0.008)], with a reciprocal increase in testosterone concentrations (60% and 56%; P <or= 0.003 for both). Plasma lipids and IGF-I concentrations were unaffected by treatment. The PK properties of the 25-mg dose showed the highest exemestane concentrations 1 h after administration, indicating rapid absorption. The terminal half-life was 8.9 h. Maximal estradiol suppression of 62 +/- 14% was observed at 12 h. The drug was well tolerated. In conclusion, exemestane is a potent aromatase inhibitor in men and an alternative to the choice of available inhibitors. Long-term efficacy and safety will need further study.
PMID: 14671195 [PubMed - indexed for MEDLINE] Free full text
Results
Study I: dose finding
Analysis of the data on hormone concentrations after the 25- and 50-mg doses showed no difference in any of the parameters measured due to an order effect; hence, the data were grouped for analysis by dose. The 25- and 50-mg doses of daily exemestane had comparable effects in suppressing circulating estrogen concentrations, with 38 ± 24% (mean ± SD; P = 0.002 vs. baseline) and 32 ± 29% (P = 0.008) decreases in estradiol concentrations, 71 ± 12% (P < 0.0001) and 74 ± 12% (P < 0.0001) decreases in estrone concentrations, and 45 ± 27% (P = 0.004) and 51 ± 20% (P = 0.02) decreases in estrone sulfate concentrations after doses of 25 and 50 mg, respectively. There was an increase in circulating testosterone concentrations after both 25 mg (60 ± 58%; P = 0.001) and 50 mg (56 ± 48%; P = 0.003) exemestane. Androstenedione concentrations were increased as well after 25 mg (32 ± 36%; P = 0.004) and 50 mg (47 ± 59%; P = 0.052) exemestane, respectively (Fig. 1***8659; and Table 2***8659
. SHBG concentrations were decreased by 21 ± 7% (P = 0.0003) and 19 ± 39% (P = 0.18) at 25 and 50 mg exemestane, respectively. Free testosterone concentrations were increased by 117 ± 74% (P = 0.0001) and 154 ± 95% (P < 0.0001) at both doses, due to the decrease in SHBG and the increase in total testosterone. No effect on circulating dehydroepiandrosterone sulfate was observed at either dose. Serum cortisol concentrations increased significantly (38 ± 39%; P = 0.008) with the 25-mg dose, but not the 50-mg dose, yet the increase was well within the normal range of cortisol concentrations. Plasma IGF-I decreased significantly (***8722;13 ± 11%; P = 0.008) after the 25-mg dose, but not the 50-mg dose. Similarly, IGF-binding protein-3 showed a trend toward lower concentrations after the 25-mg dose (***8722;7 ± 13%; P = 0.09), but not the 50-mg dose. There were no changes in circulating serum triglycerides, cholesterol, or LDL or HDL cholesterol concentrations with either dose of exemestane. Table 2***8659; summarizes the results of the hormonal and lipid data.
The mean baseline levels of estradiol and testosterone were 24.5 ± 8.8 pg/ml and 581 ± 165 ng/dl, respectively. Maximal suppression of estradiol (62 ± 14%) was observed 12 h after a single 25-mg dose of exemestane. Estradiol remained suppressed by 58 ± 21% at 24 h and returned to baseline 3***8211;6 d after treatment (Fig. 3***8659
. At the time of maximal estradiol suppression, plasma testosterone levels were unchanged and thereafter tended to increase by 32% between 2***8211;3 d; however, contrary to the significant increase in testosterone observed after 10-d daily dosing, this change did not achieve statistical significance after a single oral dose. Serum LH and FSH concentrations were measured up to 24 h at the same time intervals as the exemestane samples for the PK analysis. The mean baseline levels of LH and FSH were 4.8 ± 2.2 and 1.3 ± 0.7 mIU/ml, respectively. The percent change from baseline up to 24 h is reported in Fig. 4***8659;. The LH levels initially decreased by 26% at 2 h; thereafter, there was a tendency for an increase to a maximum of 81% at 24 h. The levels of FSH were unchanged up to 12 h and increased by 49% at 24 h.
