RT Journal Article SR Electronic T1 Nonclinical Pharmacokinetics and ADME of Givosiran, the First Approved GalNAc-conjugated RNAi Therapeutic JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP DMD-AR-2021-000381 DO 10.1124/dmd.121.000381 A1 Jing Li A1 Ju Liu A1 Xuemei Zhang A1 Valerie Clausen A1 Chris Tran A1 Michael Arciprete A1 Qianfan Wang A1 Carrie Rocca A1 Li-Hua Guan A1 Guodong Zhang A1 Diana Najarian A1 Yuanxin Xu A1 Peter Smith A1 Jing-Tao Wu A1 Saeho Chong YR 2021 UL http://dmd.aspetjournals.org/content/early/2021/05/03/dmd.121.000381.abstract AB Givosiran is a N-acetylgalactosamine (GalNAc)-conjugated RNA interference (RNAi) therapeutic that targets 5ʹ-aminolevulinate synthase 1 (ALAS1) messenger RNA (mRNA) in the liver and is currently marketed for the treatment of acute hepatic porphyria (AHP). Herein, nonclinical pharmacokinetic (PK) and absorption, distribution, metabolism, and excretion (ADME) properties of givosiran were characterized. Givosiran was completely absorbed after subcutaneous (SC) administration with relatively short plasma elimination t1/2 (less than 4 hours). Plasma exposure increased approximately dose proportionally with no accumulation after repeat doses. Plasma protein binding (PPB) was concentration dependent across all species tested and was around 90% at clinically relevant concentration in human. Givosiran predominantly distributed to the liver by asialoglycoprotein receptor (ASGPR)-mediated uptake, and the elimination t1/2 in the liver was significantly longer (~1 week). Givosiran was metabolized by nucleases, not cytochrome P450 (CYP) isozymes, across species with no human unique metabolites. Givosiran metabolized to form one primary active metabolite with the loss of 1 nucleotide from the 3ʹ end of antisense strand, AS(N‑1)3ʹ givosiran which was equipotent to givosiran. Renal and fecal excretion were minor routes of elimination of givosiran as approximately 10% and 16% of the dose was recovered intact in excreta of rats and monkeys, respectively. Givosiran is not a substrate, inhibitor, or inducer of CYP isozymes, and it is not a substrate or inhibitor of uptake and most efflux transporters. Thus, givosiran has a low potential of mediating drug-drug interactions involving CYP isozymes and drug transporters. Significance Statement Nonclinical PK and ADME properties of givosiran, the first approved GalNAc-conjugated RNAi therapeutic, were characterized. Givosiran shows similar PK and ADME properties across rats and monkeys in vivo and across human and animal matrices in vitro. SC administration results in adequate exposure of givosiran to the target organ (liver). These studies support the interpretation of toxicology studies, help characterize the disposition of givosiran in humans, and support the clinical use of givosiran for the treatment of AHP.