ABSTRACT
INTRODUCTION: This study explored the safety and tolerability features of donanemab (LY3002813) in patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild to moderate AD dementia. METHODS: Patients with AD were enrolled into the single-ascending dose phase and were administered a single, intravenous (IV) dose of donanemab (five dosing cohorts from 0.1 to 10 mg/kg) or placebo followed by a 12-week follow-up period for each dose level. After the follow-up period, the same patients proceeded into the multiple-ascending dose (MAD) phase (five cohorts) and were administered IV doses of donanemab (0.3 to 10 mg/kg) or placebo approximately once per month for up to four doses depending on the initial doses (only cohort 1 went from 0.1 mg/kg to a higher dose of 0.3 mg/kg during the MAD phase). This phase concluded with a 12-week follow-up period. The relative exposure assessment of an unblinded, single, subcutaneous 3-mg/kg dose of donanemab in patients with AD was also performed, followed by a 12-week follow-up period. One cohort of healthy subjects received an unblinded, single, IV 1-mg/kg dose of donanemab. These two cohorts did not continue to the MAD phase. RESULTS: Donanemab was generally well tolerated up to 10 mg/kg. After single-dose administration from 0.1 to 3.0 mg/kg, the mean terminal elimination half-life was ≈4 days, increasing to ≈10 days at 10 mg/kg. Only the 10-mg/kg dose showed changes in amyloid positron emission tomography. Amyloid reduction of 40% to 50% was achieved. Approximately 90% of subjects developed anti-drug antibodies at 3 months after a single intravenous dose. DISCUSSION: Intravenous donanemab 10 mg/kg can reduce amyloid deposits in AD despite having a shorter than expected half-life.
ABSTRACT
The precise role that isoflavones play in the health-related effects of soy foods, and their potential for adverse effects are controversial. This may be due in part to a lack of basic knowledge regarding their bioavailability and metabolism, particularly as it relates to the soy source. To date, there is little information concerning possible differences in the bioavailability of isoflavones derived from natural soy foods consumed at physiologically relevant intakes and whether age- or gender-related differences influence that bioavailability. In the current study of healthy adults [premenopausal (n = 21) and postmenopausal (n = 17) women and a group of men (n = 21)], we examined the effect of age, gender, and the food matrix on the bioavailability of isoflavones for both the aglycon and glucoside forms that are naturally present in 3 different soy foods, soy milk, textured vegetable protein, and tempeh. The study was designed as a random crossover trial so that all individuals received each of the 3 foods. The dose of isoflavones administered to each individual as a single bolus dose was 0.44 mg/kg body weight. Pharmacokinetic parameters were normalized to mg of each isoflavone ingested per kilogram body weight to account for differences in daidzein and genistein content between the diets. Serum isoflavone concentrations in all individuals and groups increased rapidly after the ingestion of each soy food; as expected, genistein concentrations exceeded daidzein concentrations in serum. In this small study, gender differences in peak concentrations of daidzein were observed, with higher levels attained in women. Consumption of tempeh (mainly isoflavone aglycon) resulted in higher serum peak levels of both daidzein (P < 0.001) and genistein (P < 0.01) and the associated area under the curve (P < 0.001 and P < 0.03, respectively) compared with textured vegetable protein (predominantly isoflavone glucosides). However, soy milk was absorbed faster and peak levels of isoflavones were attained earlier than with the other soy foods. Only 30% of the subjects were equol producers and no differences in equol production with age or gender were observed.
