Bioequivalence of exemestane in post-menopausal females

Abstract

The bioavailability of two exemestane tablet formulations was compared in 74 healthy post-menopausal females, aged 46 to 74 years, during a laboratory-blind, randomized, two-treatment, two-period, cross-over study under fed conditions. In each treatment phase subjects received a single dose (one tablet) of 25 mg exemestane (CAS 107868-30-4). Consecutive dosing was separated by a drug-free washout period of 21 d. Following each dosing, serial venous blood samples were collected over a period of 144 h for the determination of plasma exemestane concentrations by means of a validated LC-MS/MS method. The geometric mean Cmax of exemestane for the reference and test products was 21.48 and 20.14 ng/mL, respectively. The corresponding mean AUC(0-infinity) was 87.12 and 86.90 ng x h/mL. The median Tmax for both products under investigation appeared at 1.70 and 1.97 h, respectively. The test product was well tolerated and shown to be bioequivalent to the reference product with respect to all primary pharmacokinetic variables investigated.

Impact ofUGT2B17Gene Deletion on the Pharmacokinetics of 17-Hydroexemestane in Healthy Volunteers

“…In our pharmacokinetic study, AUC and C max of EXE and 17‐HEXE ranged from 9.2 to 40.6 ng · h/mL and 0.7 to 26.9 ng · h/mL, and from 2.2 to 13.3 ng/mL and 0.1 to 2.7 ng/mL, respectively. This indicates that our pharmacokinetic data concur with previously reported studies …”

“…Most of these studies were designed to assess the efficacy and safety of EXE following a single oral 25‐mg dose. Others were carried out to study the effects of hepatic and renal impairment or of concomitant raloxifene administration on the pharmacokinetics of EXE . In these studies the pharmacokinetic parameters of EXE and its major metabolite 17‐HEXE were calculated.…”

In Vitro Evaluation of the Interaction Potential of Irosustat with Drug-Metabolizing Enzymes

“…Because AIs could theoretically inhibit P450s involved in irosustat metabolism, however, their effects were studied in incubations of irosustat with HLMs (Table 7). Letrozole showed almost no effect on irosustat metabolism (IC 50 values were Ͼ100 M for all irosustat metabolites), and exemestane did not inhibit irosustat metabolism at up to 20 M. In both cases, these concentrations exceed by 200-fold the respective C max,ss values in humans (Pfister et al, 2001;Groenewoud et al, 2010). Anastrozole was slightly more potent than the other two AIs in inhibiting irosustat metabolism, showing IC 50 values between 34 and Ͼ100 M, depending on the irosustat metabolite (Table 7).…”

Development and validation of a sensitive liquid chromatography/tandem mass spectrometry method for the determination of exemestane in human plasma

“…The determination of exemestane in human plasma was described using HPLC with UV [3], radioimmunoassay [4] or mass spectrometric detection [5][6][7][8]. Simultaneous quantification of exemestane and its main metabolite 17-dihydroexemestane was also reported [6,7]. The described HPLC-UV method [3] is not sensitive enough (lower limit of quantification -LLOQ at 10 ng/mL) for purposes of pharmacokinetic studies in humans after a single dose administration of 25 mg exemestane tablets.…”

“…The first reported mass spectrometric method [5], similarly to HPLC-UV, is not sensitive enough (LLOQ at 1 ng/mL) for the planned study and it includes rather expensive sample preparation by solid phase extraction (SPE). The method reported by Groenewoud et al [6] does not provide details concerning both HPLC and MS conditions, therefore it is not directly reproducible. The recently published method by Corona et al [7] is based on simple sample preparation by protein precipitation and requires plasma volume of only 0.1 mL, but the LLOQ was set at 0.2 ng/mL.…”