A population pharmacokinetic and pharmacokinetic‐pharmacodynamic analysis of vupanorsen from phase I and phase II studies

Figures

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  FIGURE 1. PK/PD model schematic. Decrease (−) in production is shown in red. CL, clearance; K a, first‐order absorption rate constant; K in, first‐order rate constants; K out, first‐order turn‐over rate constant; PD, pharmacodynamic; Q, intercompartmental clearance; V c, volume of distribution.

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  FIGURE 2. The size of covariate effects and 95% CI from the full PK model. Black dots are the bootstrapped median, blue lines are 95% percentiles from bootstrap runs. Red dashed vertical lines of 0 and 1 represent the null effects of continuous (eGFR and age) and categorical covariates (the rest), respectively. ADAP, anti‐drug antibody positive; CL/F, apparent clearance; eGFR, estimated glomerular filtration rate; Q/F, intercompartment clearance; Vc/F, apparent central volume of distribution.

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  FIGURE 3. VPC in percentage change from baseline, stratified by treatment regimen for phase II studies: (a) ANGPTL3, (b) TG, (c) non‐HDL‐C. Blue dots are observed data; blue dashed and solid lines are observed 90% quantiles and median data; and blue and red shaded area the corresponding 95% CI constructed from 500 sets of simulations. Gray dashed lines represent target values. ANGPTL3, angiopoietin‐like 3; CI, confidence interval; non‐HDL‐C, non‐high density lipoprotein‐cholesterol; PD, pharmacodynamic; PI, prediction interval; PK, pharmacokinetic; Q1W, weekly; Q2W, every 2 weeks; Q4W, every 4 weeks; TG, triglycerides; VPC, visual predictive check.

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  FIGURE 4. Dose–response prediction for ANGPTL3, TG, and non‐HDL‐C, stratified by dosing interval. Efficacy targets were set a priori to −75% (blue line), −60% (green line), and 35% (red line) for ANGPTL3, TG, and non‐HDL‐C, respectively. Solid lines and shaded areas represent typical predictions and 90% CI, respectively. ANGPTL3, angiopoietin‐like 3; CFB, change from baseline; CI, confidence interval; DAYP, planned day. HDL‐C, high‐density lipoprotein cholesterol; Q2W, every 2‐weeks; Q4W, every 4 weeks; TG, triglycerides.