EFFECT OF FOOD ON THE PHARMACOKINETICS OF AZELIRAGON IN HEALTHY ADULT SUBJECTS

Abstract

Azeliragon, an oral antagonist of the Receptor for Advanced Glycation Endproducts (RAGE), is being evaluated in a pivotal Phase 3 study for efficacy and safety in patients with mild Alzheimer's disease. Azeliragon exerts a multimodal mechanism of action including effects on Aβ, tau phosphorylation, and inflammation through an initial step of blocking proteins (i.e. Aβ, S100b) from binding to RAGE. The present study evaluated the effect of an FDA high fat meal on the pharmacokinetics (PK) of the 5 mg azeliragon Phase 3 capsule formulation. This was an open-label, randomized, parallel, single-dose study to assess the effect of a high-fat meal on the pharmacokinetics of azeliragon. Subjects were randomized to receive a single dose of azeliragon 5 mg administered either following a 10-h overnight fast or within 30 minutes of the start of ingestion of a high fat meal (150 protein calories, 250 carbohydrate calories and 500–600 fat calories). Serial PK samples were collected for 312 hours following dosing. Safety assessments were performed throughout the 14-day study period. Twenty-eight (14 fasted and 14 fed) subjects (27 males, 1 female), 24 to 55 years old, were randomized, and all completed the study. Fed and fasted groups were similar for age, race, ethnicity, height, weight and BMI. Administration with food resulted in an approximately 16–20% reduction in geometric mean estimates of exposure. AUC(0-last) was 113 ng*h/mL fasted and 90 ng/*h/mL fed (ratio: 0.80, 90% CI: 0.57, 1.12). AUC(0–72h) was 38.3 ng*h/mL fasted and 32.0 ng*h/mL fed (ratio: 0.84, 90% CI: 0.70, 1.00). Cmax was 0.70 ng/mL fasted and 0.58 ng/mL fed (ratio: 0.83, 90% CI: 0.69, 1.00). Azeliragon was well tolerated with only 3 mild treatment-emergent adverse events reported (2 in fasted, 1 in fed) none of which resulted in withdrawal from study. There was an approximately 16–20% reduction in exposure (AUC(0-last), AUC(0–72h), Cmax) following administration of azeliragon 5 mg following a high fat meal. At the Phase 3 dose of 5 mg/day the magnitude of reduction is not anticipated to be clinically meaningful. Consequently, azeliragon may be given without regard to meals.