부산대학교 도서관

Aims: The aim of this study was to characterize the population pharmacokinetics of AZD8233, an antisense oligonucleotide (ASO) that targets the PCSK9 transcript to reduce hepatocyte PCSK9 protein production and plasma levels. AZD8233 utilizes generation 2.5 S‐constrained ethyl motif (cET) chemistry and is conjugated to a triantennary N‐acetylgalactosamine (GalNAc3) ligand for targeted hepatocyte uptake. Methods: A non‐linear mixed‐effect modelling approach utilizing NONMEM software was applied to AZD8233 concentration–time data from 3416 samples in 219 participants from four phase 1–2 studies, one in healthy volunteers (NCT03593785) and three in patients with dyslipidaemia (NCT04155645, NCT04641299 and NCT04823611). Results: The final model described the AZD8233 plasma concentration–time profile from four phase 1–2 studies in healthy volunteers or participants with dyslipidaemia, covering a dose range of 4 to 120 mg. The pharmacokinetics of AZD8233 were adequately described by a two‐compartment model with first‐order absorption. The supra‐proportional increase in maximum plasma concentration (Cmax) across the observed dose range was described by non‐linear Michaelis–Menten elimination (maximum elimination rate, 9.9 mg/h [12% relative standard error]; concentration yielding half‐maximal elimination rate, 4.8 mg/L [18% relative standard error]). Body weight, sex, estimated glomerular filtration rate and disease status (healthy participant vs. patient with dyslipidaemia) were identified as factors affecting exposure to AZD8233. Conclusions: Covariate analysis showed body weight to be the main factor affecting exposure to AZD8233, which largely explained the higher Cmax observed in the Asian population relative to non‐Asians. [ABSTRACT FROM AUTHOR]