NCT00766324What's known on the subject? and What does the study add?• Since their discovery aurora kinases have been identified as a potential target in anticancer therapy and currently many aurora-selective small molecule kinase inhibitors are in development. Aurora kinases play an essential role as key mitotic regulators and are frequently overexpressed in prostate cancer. In vivo data in the transgenic mouse prostate carcinoma model revealed tumour regressions of >80% in three out of 16 animals and disease stabilizations in 10 out of 16 animals treated with danusertib. Two phase I dose escalation studies with danusertib in patients with advanced solid tumours were performed, which established two doses and schedules for phase II studies. However, the preliminary data of the available phase II studies with danusertib in solid tumours showed limited activity. Danusertib may yield more activity in the treatment of leukaemias than in solid tumours. Danusertib is generally well tolerated with neutropenia as the main dose limiting toxicity.• This phase II study determined the efficacy and toxicity of danusertib administered intravenously over two different dosing schedules in patients with metastatic castration-resistant prostate cancer (CRPC) with progressive disease after docetaxel-based treatment. Danusertib showed in vivo antitumour activity in prostate cancer models and clinically relevant disease stabilizations were observed in several patients with solid tumours in phase I studies. However, our study revealed that monotherapy with danusertib, although well tolerated, showed only limited activity in the treatment of patients with CRPC. In view of the new advances in the treatment of patients with CRPC and the negative result of our study it is unlikely that danusertib will be further explored for the treatment of patients with CRPC. Further studies are required to establish specific biomarkers predictive for either response or prolonged disease stabilization to select subsets of patients with CRPC who may benefit from treatment with danusertib. Objective• To determine the efficacy and toxicity of danusertib (formerly PHA-739358) administered i.v. over two different dosing schedules with equivalent dose intensity in patients with metastatic castration-resistant prostate cancer with progressive disease after docetaxel-based treatment. Patients and Methods• In this open-label, multicentre phase II trial 88 patients were randomly assigned (1:1 ratio) to receive either danusertib 330 mg/m 2 over 6 h i.v. on days 1, 8 and 15 (arm A, n = 43) or 500 mg/m 2 over 24 h i.v. on days 1 and 15 (arm B, n = 38), every 4 weeks.• The primary endpoint chosen for this exploratory study was PSA response rate at 3 months. Results• Sixty patients (31/43 in arm A and 29/38 in arm B) were evaluable for the primary endpoint.• Median progression-free survival was 12 weeks in both arms.

2006-003772-35.

These findings suggest that the S,S-enantiomer is responsible for the hemodynamic effects of reboxetine in humans. Increases in supine blood pressure after reboxetine administration may be interpreted as regression to the mean value and not caused by any treatment effect.

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

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