5 hours with multiple doses. Fig. 3 Mean dose-normalized plasma concentrations of Org 26576 on days 1, 4, and 27 for (a) the 100 mg twice-daily dose and (b) the 400 mg twice-daily dose in MDD patients. Discussion and Conclusion The studies presented herein describe bridging data for the AMPA PAM Org 26576. On the basis of evidence suggesting that neuropsychiatric patients often tolerate higher medication doses than do
HVs, the clinical development plan for the Org 26576 program included both phase I (HVs) and phase Ib (patients diagnosed with MDD) multiple-rising-dose studies. The primary objectives were to establish the MTD and to fully characterize the safety, tolerability, and pharmacokinetics in both populations.
Proteasome structure Although the trials differed in several design elements, we believe that the data presented here are both comparable and interpretable, given that they are based on trial cohorts that included the same multiple-rising-dose approach, starting dose, and regimen; nearly identical JNK-IN-8 titration steps; similar housing conditions; and a similar safety assessment strategy. In the HV trial, Org 26576 was well tolerated at doses of up to 225 mg bid, while in depressed patients, the MTD was 450 mg bid – twice the maximum dose established in HVs. The patient trial also established that slightly faster titration could be achieved without increasing the number of dose-limiting AEs. The most common AEs associated with the study drug in both populations included dizziness, nausea,
and feeling drunk. There were no clinically relevant safety issues associated with Org 26576 at any Demeclocycline dose in either population. In an attempt to learn whether better tolerability in patients could be explained by pharmacokinetic differences between populations, we examined pharmacokinetic parameters for both HVs and patients under highly comparable RGFP966 dosing conditions. Multiple-dose administration of Org 26576 at the same dose level in HVs and MDD patients resulted in pharmacokinetic profiles that were similar overall, though not identical. In both populations, Org 26576 was rapidly absorbed and disposed, with a t1/2 not longer than 3 hours. Cmax and tmax values increased sub-proportionally and underwent a time delay, suggesting a dose-dependent, partially saturated absorption process, although not statistically significant. Further, no regimen effects were observed, indicating linear kinetics over time. The overall exposure of the drug, however, seemed to be somewhat higher and tmax values seemed to be greater in patients than in HVs. While the origin of the exposure difference is unclear, food and formulation effects cannot be entirely excluded as underlying causes of the tmax difference. Indeed, one of the principal limitations in this population comparison is the difference between studies under fed/fasted conditions.