0% and CL/F was estimated with 22.1% imprecision. As can be seen in table IX, various designs were tested, but the greatest improvement came when the spread of the timing of the samples over the dosing interval was as wide as possible across the visits (design no. 8), and the criterion ratio was 25.8% and CL/F was estimated with 6.2% imprecision. Allowing more than one sample to be taken on one of the visits (design nos. 11 and 12) did not improve the

criterion ratio or improve the precision with which CL/F was estimated, probably because a design with five samples per subjects was already adequate as a sparse sample design. Selumetinib cell line Discussion After single and daily repeated administration, GLPG0259 was slowly absorbed and eliminated. On the basis of a statistical ANOVA, the exposure to GLPG0259 increased in proportion to the dose over a 30–150 mg single-dose range and a 25–75 mg this website repeated-dose range. In the population pharmacokinetic model developed with data from the three first phase I studies, the Frel for GLPG0259 increased with increasing dose, while the ka decreased

with increasing dose up to 50 mg and was then reasonably constant. Conversely to the conclusion drawn from the ANOVA on dose-normalized parameters, these changes in Frel and ka detected during the development of the population pharmacokinetic model would be a sign of non–dose-proportional pharmacokinetics. It is not unusual to observe deviation from dose proportionality within a dose range as wide as 1.5–150 mg. In addition, a population approach is much more sensitive than standard statistical analysis for finding and characterizing dose non-linearity.[16] More data would be needed, especially at higher dose levels, to refine the model and the relation of ka and Frel to the dose to draw definitive conclusions on the dose linearity of GLPG0259 pharmacokinetics. The most frequently reported AEs following repeated administration with GLPG0259 were related to gastrointestinal disorders (loose stools, nausea,

abdominal pain, or discomfort). These events, reported only at doses of 50 mg and higher, could be explained by the residence time of GLPG0259 in the gastrointestinal tract. Indeed in a whole-body Dimethyl sulfoxide autoradiography with [14C]-radiolabeled compound administered in a mouse model (3 mg/kg [14C]-GLPG0259), a huge amount of radioactivity was localized 4 and 8 hours postdose in the small and large intestine contents, as well as in the gallbladder, suggesting slow and incomplete absorption and/or intestinal secretion directly or via the bile (data not shown). Apart from gastrointestinal disorders, no systemic AEs were reported after repeated dosing with GLPG0259. Thus an increase in Frel with increasing dose should not be of concern as long as systemic exposure in humans remains below the ‘no observed adverse effect level’ (NOAEL) exposures in animal species.