Population Pharmacokinetics and Exposure-Response Modeling for Evinacumab in Children, Adolescents, and Adults With...

Evinacumab, an angiopoietin-like 3 (ANGPTL3) inhibitor, significantly reduces low-density lipoprotein cholesterol (LDL-C), independent of low-density lipoprotein receptor, in patients with homozygous familial hypercholesterolemia (HoFH). A population pharmacokinetic (PK)/pharmacodynamic (PD) model was previously developed to characterize evinacumab exposure and LDL-C response in adolescents and adults. In this analysis, the PK/PD model was refined to include children aged 5 to < 12 years and to characterize the lipoprotein apheresis effect on LDL-C reduction. The PK of evinacumab was characterized by a two-compartment model with parallel linear and non-linear elimination. Linear disposition parameters were allometrically scaled by body weight. Baseline ANGPTL3 concentrations and disease status (non-HoFH vs. HoFH) influenced the maximum target-mediated rate of elimination but had a minimal effect on evinacumab exposures at 15 mg/kg intravenous doses every 4 weeks across weight/age groups. In patients with HoFH, the LDL-C reduction was adequately described by an indirect response model in which evinacumab inhibits the formation of LDL-C and that includes a secondary elimination process quantifying the lipoprotein apheresis effect. Older age was associated with a decrease in baseline LDL-C. An increase in body weight was associated with a reduction in the maximum inhibitory effect of evinacumab. Model-based simulations showed that while evinacumab exposure is reduced with decreasing age/body weight, younger patients are predicted to have a comparable or greater magnitude of LDL-C reduction than older patients at a dose of 15 mg/kg. Overall, the model adequately predicted the evinacumab exposure and LDL-C reduction in children, adolescents, and adults with HoFH, aligning with clinically relevant observations.