Your browser doesn't support javascript.
loading
Evaluation of the distribution and excretion of [14C]-inclisiran following single subcutaneous administration in cynomolgus monkeys.
Lehoux, Dario; Far, Adel Rafai; Kallend, David; Wijngaard, Peter L J; Zerler, Brad.
Afiliação
  • Lehoux D; Targanta Therapeutics Inc., a wholly owned subsidiary of The Medicines Company, Saint Laurent, Quebec H4S 2A1, Canada.
  • Far AR; Targanta Therapeutics Inc., a wholly owned subsidiary of The Medicines Company, Saint Laurent, Quebec H4S 2A1, Canada. Electronic address: adel.rafai_far@novartis.com.
  • Kallend D; The Medicines Company (Schweiz) GmbH, Zurich 8001, Switzerland.
  • Wijngaard PLJ; The Medicines Company Inc., Parsippany, NJ 07054, USA.
  • Zerler B; The Medicines Company Inc., Parsippany, NJ 07054, USA.
Toxicol Appl Pharmacol ; 443: 115978, 2022 05 15.
Article em En | MEDLINE | ID: mdl-35288146
ABSTRACT
Inclisiran is a small interfering RNA molecule that was designed to reduce plasma low-density lipoprotein cholesterol (LDL-C) levels by inhibiting proprotein convertase subtilisin/kexin type 9 synthesis in the liver. This study aimed to characterize the tissue distribution and excretion of inclisiran after dosing in monkeys. A single 20 mg/kg subcutaneous injection of [14C]-inclisiran was administered to 12 male cynomolgus monkeys. Plasma concentrations and tissue binding parameters for inclisiran were assessed up to 42 days after injection using liquid scintillation of blood samples and tissue homogenates, as well as quantitative whole-body autoradiography. Radioactivity was highest in the liver at all time points from 24 h onward and remained elevated throughout the entire study period. Radioactivity was also detected in the kidneys and bladder wall, returning to low levels by 24 h. The concentration of radioactivity in the liver (402.97 µg equivalent/g) was 15.7-fold higher than in the kidneys (25.70 µg equivalent/g). Very low amounts of radioactivity were detected in all other tissues examined. The highest radioactivity in tissue homogenates was in the liver and kidney pyramid (327 and 351 µg equivalent/g, respectively). This study confirmed the selective uptake of inclisiran by the liver, indicating that the N-acetylgalactosamine linker allows for selective uptake via the asialoglycoprotein receptors expressed on hepatocytes compared with other tissues that lack asialoglycoprotein receptors. The long tissue retention in the liver supports the infrequent, biannual dosing schedule for inclisiran in the clinic and the temporal disconnect between short-term systemic exposure and sustained lowering of LDL-C.
Assuntos
Palavras-chave

Texto completo: 1 Base de dados: MEDLINE Assunto principal: RNA Interferente Pequeno Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: RNA Interferente Pequeno Idioma: En Ano de publicação: 2022 Tipo de documento: Article