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Abstract
Donanemab is an amyloid-targeting therapy that resulted in robust amyloid plaque reduction
and slowed Alzheimer's disease (AD) progression compared with placebo in the phase
II TRAILBLAZER-ALZ study (NCT03367403). The objectives of the current analyses are
to characterize (i) the population pharmacokinetics of donanemab, (ii) the relationship
between donanemab exposure and amyloid plaque reduction (response), and (iii) the
relationship between donanemab exposure and amyloid-related imaging abnormalities
with edema or effusions (ARIA-E). Model development included data from participants
with mild cognitive impairment or mild to moderate dementia due to AD from the phase
Ib study on donanemab (NCT02624778) and participants with early symptomatic AD from
the TRAILBLAZER-ALZ study. The analysis showed donanemab has a terminal elimination
half-life of 11.8 days. Body weight and antidrug antibody titer impact donanemab exposure
but not the pharmacodynamic response. Maintaining a donanemab serum concentration
above 4.43 μg/mL (95% confidence interval: 0.956, 10.4) is associated with amyloid
plaque reduction. The time to achieve amyloid plaque clearance (amyloid plaque level
< 24.1 Centiloids) varied depending on the baseline amyloid level, where higher baseline
levels were associated with fewer participants achieving amyloid clearance. The majority
of participants achieved amyloid clearance by 52 weeks on treatment. Apolipoprotein
ε4 carriers, irrespective of donanemab serum exposure, were 4 times more likely than
noncarriers to have an ARIA-E event by 24 weeks.