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

Abstract

AimsExemestane (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. MethodsThis 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 P K 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. ResultsA three-compartment model with first-order elimination rate best described exemestane disposition ( k 12 0.454, k 21 0.158, k 13 0.174, k 31 0.016 and k 0.738 h -1 ). Absorption was described by a mono-exponential function [ k a 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 C 50 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. ConclusionsExemestane 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. Correspondence

Evaluation of the effect of food on the pharmacokinetics of axitinib in healthy volunteers

“…The spectrum of effects that has been associated with changes in formulation includes variable impact of food on drug absorption [10], altered bioavailability [11,12] including altered drug absorption [13,14], and even potential changes in the delivery to tumor target site [12,15]. Initial trials in the axitinib clinical development program were conducted using tablets containing crystal polymorph axitinib Form IV FCIR of axitinib drug substance [1,[3][4][5][16][17][18].…”

Detection of new exemestane metabolites by liquid chromatography interfaced to electrospray-tandem mass spectrometry

“…Three suspect signals were detected in all urine samples except in blank urines from the same subjects (Figs. [2][3][4] and their ESI product ion mass spectra are shown (Figs. 5-7).…”

“…Aromatase is a cytochrome P450 enzyme which catalyzes estrogen formation (estrone and estradiol) from androgens (androstenedione and testosterone). This drug is used clinically in postmenopausal women with advanced hormone dependent breast cancer refractory to tamoxifen treatment [3,4].…”

A dose-ranging study of the pharmacokinetics and pharmacodynamics of the selective apoptotic antineoplastic drug (SAAND), OSI-461, in patients with advanced cancer, in the fasted and fed state

“…The addition of a high-fat meal results in increased bile secretion capable of increasing drug solubility, increased lymphatic uptake resulting in decreased first-pass effect, slowed gastric emptying which prolongs the retention of the drug and increased intestinal motility [32]. Other anticancer agents whose bioavailability are increased with food include exemestane (1.6-fold higher), danazol (threefold higher), and retinods, such as fenretinide (3.4-fold higher) [2,5,38]. The effect of food on the relationship of PK parameters and pharmacodynamic response seen with OSI-461 potentially explains the increased gastrointestinal toxicity and the increases in pGSK-3β seen predominantly at higher dose levels.…”