S-Plus version 6.2 software was used for exploratory graphical analysis. R software (version 2.12.2)[12] was used for evaluation of goodness of fit and model evaluation. The program WinPOPT (version 1.2.1)[13] was used to aid selection of the timing and number of samples to be taken per patient in phase II. Results Safety and Tolerability With the exception of a single subject

who discontinued GW786034 in vitro study 1 because of a nephrolithiasis while on placebo (reported as a serious AE [SAE]), all subjects completed the studies. The four studies showed a consistent pattern of AEs. Nausea, abdominal discomfort, and loose stools were the most frequently reported AEs, showing a dose-related pattern of incidence and severity from a dose of 50 mg upward. The feeding status ARN-509 cell line or type of formulation had no influence on these

AEs. All other AEs were typical phase I environment events, such as somnolence, fatigue, headache, oropharyngeal pain, and nasopharyngitis. No clinically relevant trends or changes were observed in the median laboratory and urinalysis values over time. A single case of a mild alanine aminotransferase increase was observed in a subject at the 75 mg dose in the second study. Across the four studies, no clinically relevant trends or changes were observed in the median vital sign values and ECG parameters over time. No treatment-emergent abnormalities related to vital signs or ECG parameters were observed in more than one subject during the trials. None of the abnormalities related to vital signs or ECG parameters were considered clinically relevant by the investigators. After multiple dosing, the maximum tolerated dose was established as being 50 mg once daily. GLPG0259 Single-Dose Pharmacokinetics (Study 1) GLPG0259 plasma concentration–time data are plotted in figures 1 and 2 (linear and semi-logarithmic plots), and the pharmacokinetic Arachidonate 15-lipoxygenase parameters are listed in table I. At the three lowest doses (up to 15 mg), λz could not be reliably estimated in most of the subjects, because of insufficient datapoints to characterize the terminal

elimination phase. In addition, for some subjects at the highest doses (≥30 mg), the AUC∞ was poorly estimated, with an extrapolated AUC from 24 hours to infinity that represented more than 20% of the total AUC. Consequently, the t1/2,λz and AUC∞ of these subjects were not included in the summary statistics, and no inferential statistical Blasticidin S nmr analysis was performed on these two parameters. After a single oral administration to healthy, fed subjects, GLPG0259 was absorbed slowly, with the median tmax increasing with the dose from 2 to 7 hours (table I). The terminal plasma elimination phase of GLPG0259 was parallel for doses ≥30 mg and displayed a monophasic profile (figure 1). Table I GLPG0259 pharmacokinetic parameters after a single oral dose in fed healthy subjects (n = 6 per dose group) Fig.