Exemestane pharmacokinetics

The pharmacokinetics of a single oral dose of exemestane 25 mg have been studied in postmenopausal subjects with normal hepatic function (n = 9), moderately impaired hepatic function (n = 9), severely impaired hepatic function (n = 8), normal renal function (n = 6), moderately impaired renal function (n = 6), and severely impaired renal function (n = 7) (36). Exposure to exemestane was increased two- to three-fold in patients with hepatic impairment the apparent oral clearance and apparent volume of distribution of exemestane were reduced. Renal impairment was also associated with two- to three-fold increases in exposure due to reduced clearance. However, because exemestane has a relatively large safety margin, the authors considered that these effects were of no clinical significance. 

Jannuzzo MG, Poggesi I, Spinelli R, Rocchetti M, Cicioni P, Buchan P. The effects of degree of hepatic or renal impairment on the pharmacokinetics of exemestane in postmenopausal women. Cancer Chemother Pharmacol 2004 53(6) 475-81. 

The manufacturers say that in vitro evidence shows that while exemestane is metabolised by both the cytochrome P450 isoenzyme CYP3A4 and al-doketoreductases, a clinical study found that ketoconazole (a specific inhibitor of CYP3A4) had no significant effects on the pharmacokinetics of exemestane. The manufacturers therefore suggest that interactions with CYP3A4 enzyme inhibitors are uniikeiy. ... 

In 6 menopausal women with breast cancer aminoglutethimide 250 mg four times daily for 6 weeks markedly reduced the serum levels of tamoxifen 20 to 80 mg daily and most of its metabolites. The clearance of the tamoxifen was inereased by 3.2-fold and the tamoxifen AUC was re-dueed by 73% (range 56 to 80%). Conversely, the concurrent use of anastrozole 1 mg daily for 28 days did not affect the pharmacokinetics of tamoxifen in a double-blind, placebo-controlled study in 34 women with breast eaneer who had been taking tamoxifen 20 mg daily for at least 10 weeks. Similarly, letrozole 2.5 mg daily had no effeet on the pharma-eokineties of tamoxifen in 18 women taking tamoxifen 20 mg daily. Further, a study in 32 women clinically disease-free following primary treatment for breast eaneer and who had been taking tamoxifen 20 mg daily for at least 4 months found that exemestane 25 mg daily for 8 weeks... 

Tamoxifen 20 to 80 mg daily did not alter the pharmacokineties of aminoglutethimide 250 mg four times daily. In a pilot study, 18 postmenopausal women with breast cancer were gi ven exemestane 25 mg daily for 14 days, then exemestane and tamoxifen 20 mg daily for 4 weeks. Tamoxifen did not affect the pharmacokinetics (plasma levels) or pharmacodynamics (estrone, estrone sulfate and estradiol suppression) of exemestane and the eombination was well-tolerated. In 12 women letrozole levels were reduced by 38% (range 0 to 70%) 6 weeks after tamoxifen 20 mg daily was added to letrozole 2.5 mg daily. This redue-tion persisted after 4 to 8 months however, the estradiol suppressant effeets of letrozole did not appear to be affected. Similarly, although the estradiol suppressant effects of anastrozole 1 mg daily did not appear to be affeeted by tamoxifen 20 mg daily in two studies, in one of these studies, anastrozole levels were deereased by 27% by tamoxifen. ... 

Rivera E, Valero V, Francis D, Asnis AG, SchaafLJ, Duncan B,Hoitobagyi GN. Pilot stutfy evaluating the pharmacokinetics, i iarmacotfynamicsi, and safety of the cembination of exemestane and tamoxifen. Clin Cancer Res (2004) 10,1943-8. 

Traina TA, Poggesi I, Robson M, Asnis A, Duncan BA, Heerdt A, Dang C, Lake D, Moasser M, Panageas K, Borgen P, Norton L, Hudis C, Dickler MN. Pharmacokinetics and tolerability of exemestane in combination with raloxifene in postmenopausal women with a history of breast cancer. Breast Cancer Res Treat 2008 111(2) 377-88. 

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