FIGURE 1.

Schematic of the population PK and PK/PD models for lecanemab. CL, clearance; K _in, zero‐order rate constant for production of biomarker; K _out, first‐order rate constant of degradation of biomarker; PD, pharmacodynamic; PK, pharmacokinetic; Q, intercompartmental clearance; V ₁, central volume of distribution; V ₂, peripheral volume of distribution. The equation for standard uptake ratio (SUVr) PK/PD model is presented below: $\frac{\text{dSUVr}}{\mathrm{dt}}={\mathrm{K}}_{\text{in}}-\text{SUVr}\left(t\right)\bullet {\mathrm{K}}_{\text{out}}\bullet \left[1+\frac{{\mathrm{E}}_{\max }\bullet \text{Conc}}{{\mathrm{EC}}_{50}+\text{Conc}}\right]$ Estimated parameters included baseline SUVr, the zero‐order production rate constant of amyloid plaque (K _in), maximum exposure effect (E _max), and lecanemab concentration resulting in half of the maximum drug effect (EC₅₀), where K _out = K _in/baseline. The equations for Aβ42/40 ratio and p‐tau181 models are presented below: $\begin{array}{c}\mathbf{A\beta }\mathbf{42}/\mathbf{40}\mathbf{\text{ratio:}}\frac{\mathrm{dR}}{\mathrm{dt}}={\mathrm{K}}_{\text{in}}\bullet \left[1+\text{Slope}\bullet \text{Conc}\right]-\mathrm{R}\left(t\right)\bullet {\mathrm{K}}_{\text{out}}\hfill \end{array}$ $\begin{array}{c}\mathbf{p}\mathbf{-}\mathbf{tau}\mathbf{181:}\frac{\mathrm{dR}}{\mathrm{dt}}={\mathrm{K}}_{\text{in}}\bullet \left[1-\text{Slope}\bullet \text{Conc}\right]-\mathrm{R}\left(t\right)\bullet {\mathrm{K}}_{\text{out}}\hfill \end{array}$ For both Aβ42/40 ratio and p‐tau181 estimated parameters included baseline, first order degradation rate constant of biomarker (K _out) and slope for exposure effect, where K _in = K _out * baseline.