P1-240: The effect of concomitant administration of multiple doses of avagacestat on the pharmacokinetics of either donepezil or galantamine in healthy subjects

Avagacestat is a selective g-secretase inhibitor in clinical development for the treatment of Alzheimer's Disease. Avagacestat weakly-to-moderately inhibits 2 cytochrome P450 (CYP) enzymes, CYP3A4 and CYP2D6. The objective of these studies was to assess the effect of concomitant administration of multiple doses of avagacestat on the pharmacokinetics of donepezil and galantamine, 2 acetylcholinesterase inhibitors metabolized by CYP3A4 and CYP2D6. Each study was an open-label, single-sequence, multiple-dose, one-way interaction study. In one study, subjects were given donepezil 5 mg daily for 14 days, followed by a 14-day period where donepezil was co-administered daily with 125 mg avagacestat. In the second study, 8 mg galantamine was administered daily for 7 days, then 16 mg daily for 7 days, followed by a co-administration period of 10 days with 125 mg avagacestat. 32 and 34 subjects were randomized in the donepezil and galantamine study, respectively. Coadministration of avagacestat and donepezil or galantamine was associated with an increase in the geometric mean Cmax (14-21%) and AUC(TAU) (24-26%) of donepezil and/or galantamine; an increase not likely to be clinically relevant. One serious adverse event (SAE) was reported in healthy subjects co-administered avagacestat and galantamine for 10 days. On Day 25, a subject was found to have elevated lipase (5x ULN) and amylase (2x ULN) and was diagnosed with pancreatitis. The subject, who also had multiple gall stones, was admitted to the hospital, was treated, and recovered fully. Co-administration of avagacestat with either donepezil or galantamine in healthy subjects for short periods of time was associated with a higher frequency of AEs than administration of donepezil or galantamine alone. The most common AEs in either study included headache, nausea, and epistaxis. Most AEs were mild in nature and all, except nasal congestion, resolved prior to study discharge. Co-administration of multiple 125 mg doses of avagacestat (the highest dose tested in phase IIb studies) and either donepezil or galantamine at steady-state appeared to be generally well tolerated in healthy subjects. Co-administration of avagacestat was not associated with clinically relevant increases in Cmax or AUC for either donepezil or galantamine.