4 GLPG0259 pharmacokinetic profiles after a single oral dose of GLPG0259 given to healthy subjects as (a) free-base oral solution in the fasted and fed states; (b) free-base oral solution in the fasted state and fumarate salt capsules in the fasted and fed states; or (c) fumarate salt capsules in the fed state and free-base solid dispersion
capsules in the fed state. Compared with GLPG0259 free-base oral solution, the bioavailability (both Cmax and AUC∞) of a single 50 mg dose of Pitavastatin GLPG0259 given as the fumarate salt in Ruboxistaurin nmr capsule form in the fasted state was decreased by about 45% (table VII). No change in the absorption rate (tmax 6 versus 7 hours) or t1/2,λz (31.6 versus 29.6 hours) was noted. This decrease in bioavailability was prevented by dosing the GLPG0259 fumarate salt capsule in the fed state (figure 4b). In such conditions, the solid dosage form led to bioavailability comparable to that obtained with the GLPG0259 free-base oral solution administered in fasted conditions, as shown by a Cmax of 15.2 ng/mL (versus MRT67307 in vitro 12.8 ng/mL) and an AUC∞ of 542 ng · h/mL (versus 536 ng · h/mL) [table V].
Table VII Table VII. Statistical analysis of the formulation effect on GLPG0259 pharmacokinetic parameters Finally, a-head-to-head comparison of two solid dosage forms was investigated after a single 50 mg dose was given in the fed state as capsules of GLPG0259 fumarate salt and GLPG0259 free-base solid dispersion as coated pellets. The two formulations compared well, as shown by Cmax values of 20.4 ng/mL versus 19.8 ng/mL and AUC∞ values of 713 ng · h/mL versus 670 ng · h/mL for the free-base solid dispersion and fumarate salt, respectively (table V), with corresponding point estimates of 103.73% (90% CI 93.73, 114.81) and 107.80% (90% CI 99.76, 116.50), respectively (table VI). Even if these three studies were not powered to compare formulations, using the 90% CI approach, the interval boundaries for both Cmax and AUC were close to or even fell within (study 4) the 80–125% bioequivalence
range. Population Exoribonuclease Pharmacokinetics of GLPG0259 The exploratory graphical analysis from study 1 (a single ascending dose) revealed that the elimination of GLPG0259 was independent of the dose, but that the dose-normalized profiles were not superimposable within the entire dose range (1.5–150 mg), that tmax occurred later at higher doses, and that there appeared to be no influence of food on the absorption of the solution formulation. After multiple doses, steady-state GLPG0259 plasma concentrations were reached after 4–5 days. The dose non-linearity observed after single dose administration was not apparent after multiple doses where a smaller dose range of 25–75 mg was given (data not shown).
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