Combined Semi-mechanistic Target-Mediated Drug Disposition and Pharmacokinetic–Pharmacodynamic Models of Alirocumab, PCSK9, and Low-Density Lipoprotein Cholesterol in a Pooled Analysis of Randomized Phase I/II/III Studies

Figures

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  Fig. 1. Schematic representation of the semi-mechanistic population pharmacokinetic–pharmacodynamic model describing alirocumab, PCSK9 and LDL-C. PCSK9, proprotein convertase subtilisin kexin type 9 LDL-C; LDL-C, low-density lipoprotein cholesterol; kcp/kpc, transfer constants between the central and peripheral compartments; ka, rate constant of absorption, if subcutaneous administration; In(t), infusion rate, when administered intravenously; kel, free alirocumab elimination rate constant; SC, subcutaneous; IV, intravenous; ksyn, PCSK9 zero-order rate of synthesis; kdeg, PCSK9 first-order rate of degradation; kon, association rate constant of the drug–target complex; koff, complex dissociation rate constant; kclear, rate constant for complex clearance; Imax, maximal capacity of inhibition of LDL-C degradation; IC50, concentration of free PCSK9 necessary to reach half of Imax; γ, Hill coefficient; kout, first-order LDL-C degradation rate constant during treatment; kout(0), first-order LDL-C degradation rate constant before alirocumab

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  Fig. 2. Effects of the inclusion of covariate–parameter relationships on alirocumab exposure and on the reduction of the LDL-C level. a Effect of co-administration of statins on Imax, kout, and V. b Effect of baseline total PCSK9—less than the 25th percentile (p25) or higher than the 75th percentile (p75)—on IC50 and kdeg. c Effect of sex on Imax. V, volume of distribution; kout(0), first-order LDL-C degradation rate constant before alirocumab; Imax, maximal capacity of inhibition of LDL-C degradation by PCSK9; kout, first-order LDL-C degradation rate constant during treatment; kdeg, PCSK9 first-order rate of degradation; kon, association rate constant of the drug–target complex; IC50, concentration of free PCSK9 necessary to reach half of Imax

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  Fig. 3. Comparison of observations and (individual) predictions of total alirocumab (a), total PCSK9 (b), and LDL-C (c) of final model in a logarithmic scale. d Subplot of conditional weighted residuals (CWRES) versus population predictions for total alirocumab (focused on concentrations < 250 nM) of the final model. PRED population predictions, IPRED individual predictions, PCSK9 proprotein convertase subtilisin kexin type 9 LDL-C, LDL-C low-density lipoprotein-cholesterol

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  Fig. 4. Simulation for the effect of dose on the unbound PCSK9 and consequently on the LDL-C lowering. a Simulation of alirocumab concentration (nM) versus time (day). b Simulation of free PCSK9 concentration (nM) versus time (day). c LDL change from baseline (%) after: 75 mg subcutaneous administration, every 14 days (red line), 150 mg subcutaneous administration, every 14 days (green line), and 300 mg subcutaneous administration, every 28 days (blue line). PCSK9 proprotein convertase subtilisin kexin type 9 LDL-C, LDL-C low-density lipoprotein cholesterol