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.