title: Disposition and Pharmacokinetics of a GalNAc3-Conjugated Antisense Oligonucleotide Targeting Human Lipoprotein (a) in Monkeys.
abstract: Triantennary N-acetyl galactosamine (GalNAc3)-conjugated antisense oligonucleotides (ASOs) have greatly improved potency due to receptor-mediated uptake into hepatocyte. The disposition and pharmacokinetics of ISIS 681257, a GalNAc3-conjugated ASO, were studied in monkeys. Following subcutaneous (SC) injection, ISIS 681257 was rapidly absorbed into the systemic circulation, with peak plasma levels observed within hours after dosing. After reaching Cmax, plasma concentrations rapidly declined in a multiexponential manner and were characterized by a dominant initial rapid distribution phase in which drug transferred to tissues from circulation, followed by a much slower terminal elimination phase (half-life of 4 weeks). Intact ISIS 681257 is the major full-length oligonucleotide species in plasma (≥70%). In tissues, the conjugated-GalNAc sugar moiety was rapidly metabolized, leaving the fully unconjugated form as the only full-length oligonucleotide detected at 48 h after dosing. Unconjugated ISIS 681257 cleared slowly from tissues with a half-life of 4 weeks. ISIS 681257 was highly bound to plasma proteins (>97% bound), which limited its urinary excretion. Disposition of ISIS 681257 in plasma and liver appeared nonlinear over the 1-40 mg/kg dose range studied. The plasma and liver tissue concentration data were well described by a population based mixed-effects modeling approach with Michaelis-Menten uptake from plasma to liver. Safety data from the study and the good exposure, as well as the extended half-life of the unconjugated ASO in the liver, support further development and less frequent dosing in Phase I clinical study.
authors: Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors: Rosie Z
authors: RZ
authors: Yu
authors: Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors: Rudy
authors: R
authors: Gunawan
authors: Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors: Noah
authors: N
authors: Post
authors: Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors: Thomas
authors: T
authors: Zanardi
authors: Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors: Shannon
authors: S
authors: Hall
authors: Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors: Jennifer
authors: J
authors: Burkey
authors: Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors: Tae-Won
authors: TW
authors: Kim
authors: Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors: Mark J
authors: MJ
authors: Graham
authors: Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors: Thazha P
authors: TP
authors: Prakash
authors: Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors: Punit P
authors: PP
authors: Seth
authors: Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors: Eric E
authors: EE
authors: Swayze
authors: Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors: Richard S
authors: RS
authors: Geary
authors: Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors: Scott P
authors: SP
authors: Henry
authors: Ionis Pharmaceuticals, Inc. , Carlsbad, California.
authors: Yanfeng
authors: Y
authors: Wang
mesh_terms: D000116:Acetylgalactosamine / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D005260:Female; D006001:Glycoconjugates / Q000378:metabolism / Q000493:pharmacokinetics*; D006207:Half-Life; D022781:Hepatocytes / Q000378:metabolism; D007279:Injections, Subcutaneous; D017270:Lipoprotein(a) / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D016376:Oligonucleotides, Antisense / Q000378:metabolism / Q000493:pharmacokinetics*; D054735:Phosphorothioate Oligonucleotides / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding; D059367:RNA Cleavage
chemical_list: D001798:Blood Proteins; D006001:Glycoconjugates; D017270:Lipoprotein(a); D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D000116:Acetylgalactosamine
keywords: ASO; GalNAc3; ISIS 681257; antisense; disposition; lipoprotein; oligonucleotide; pharmacokinetics