P4-406: Tarenflurbil (MPC-7869), a selective Aβ42-lowering agent, has no significant effect on drugs metabolized by CYP2C9

Abstract

Alzheimer's disease is the most common type of dementia among the elderly. Its histopathologic features include phosphorylated Tau neurofibrillary tangles and amyloid beta senile plaques. In randomized, double-blind Phase II studies, the Selective Aβ42-Lowering Agent (SALA) tarenflurbil (MPC-7869) has demonstrated efficacy and tolerability. In earlier studies, CYP2C9 inhibition was demonstrated in vitro. Therefore, tarenflurbil has the potential to inhibit CYP2C9 in vivo. Sixteen healthy subjects participated in this third-party blind, placebo-controlled, randomized, crossover, Phase I study. Participants received either placebo or two 400-mg oral tablets of tarenflurbil every 12 hours for 9 consecutive days. On Day 6, each subject received one 500-mg oral tablet of tolbutamide, a CYP2C9 probe substrate. After the 14-day washout period, the treatments were switched (ie, subjects received the other treatment). Blood samples were collected throughout the study. Blood and urine samples were obtained on Day 6, prior to the morning dose of tarenflurbil or placebo and tolbutamide, and throughout the 96 hours after tolbutamide administration. The 90% confidence intervals for tolbutamide AUC(0–∞) (110%–120%) and Cmax (88%–112%) were within the standard bioequivalence criteria (80%–125%). Five days after administration of tarenflurbil 800 mg BID, the difference between mean tolbutamide exposure AUC(0–∞) with and without tarenflurbil was less than 15%. Furthermore, the formation clearance of 4-hydroxytolbutamide was similar for the treated and untreated states. Tarenflurbil has low potential for inhibition-based metabolic drug-drug interactions. Because of its amyloid-lowering properties, tarenflurbil holds promise as a disease-modifying agent for Alzheimer's disease.