Pharmacokinetics and Bioequivalence of Branded and Generic Formulations of Dofetilide 0.5-mg Capsules After Single-Dose Administration in Healthy Subjects.

Class III antiarrhythmics are preferred therapy for managing atrial fibrillation/flutter. Dofetilide 0.5-mg capsules were US Food and Drug Administration (FDA) approved in 1999 to treat atrial fibrillation/flutter. Bioequivalence of generic dofetilide is important for treating arrhythmias because drug concentrations must be consistent to maintain normal sinus rhythm. Generic dofetilide 0.5-mg capsule pharmacokinetics were compared with branded product in 2 open-label, 2-way crossover, single-dose studies - 1 study each in fasted and fed healthy subjects. Blood samples were collected before and up to 48 hours after dosing. Safety was assessed by tabulating adverse events and vital signs. Seventy-three subjects were enrolled; 59 completed the studies. In fasted subjects, the 90% confidence intervals (CIs) for generic dofetilide 0.5 mg versus the reference formulation were 0.996-1.026 for the area under the plasma concentration-time curve from 0 to infinity (AUC) and 0.974-1.066 for the maximum observed concentration (Cmax ). In fed subjects, the 90%CIs for AUC and Cmax were 0.988-1.015 and 0.928-0.992, respectively. All ratios were within the FDA-established bioequivalence range. Twenty-six subjects experienced 37 adverse events (generic, 15; reference, 22); all but 1 were mild or moderate in severity. Generic dofetilide 0.5-mg capsules can be considered bioequivalent to the reference product.

An evaluation of MSDC-0160, a prototype mTOT modulating insulin sensitizer, in patients with mild Alzheimer's disease.

Alzheimer's disease (AD) is associated with insulin resistance and specific regional declines in cerebral metabolism. The effects of a novel mTOT modulating insulin sensitizer (MSDC-0160) were explored in non-diabetic patients with mild AD to determine whether treatment would impact glucose metabolism measured by FDG-PET in regions that decline in AD. MSDC-0160 (150 mg once daily; N=16) compared to placebo (N=13) for 12 weeks did not result in a significant difference in glucose metabolism in pre-defined regions when referenced to the pons or whole brain. However, glucose metabolism referenced to cerebellum was maintained in MSDC-0160 treated participants while it significantly declined for placebo patients in anterior and posterior cingulate, and parietal, lateral temporal, medial temporal cortices. Voxel-based analyses showed additional differences in FDG-PET related to MSDC-0160 treatment. These exploratory results suggest central effects of MSDC-0160 and provide a basis for further investigation of mTOT modulating insulin sensitizers in AD patients.