PT  - JOURNAL ARTICLE
AU  - Jing Li
AU  - Ju Liu
AU  - Xuemei Zhang
AU  - Valerie Clausen
AU  - Chris Tran
AU  - Michael Arciprete
AU  - Qianfan Wang
AU  - Carrie Rocca
AU  - Li-Hua Guan
AU  - Guodong Zhang
AU  - Diana Najarian
AU  - Yuanxin Xu
AU  - Peter Smith
AU  - Jing-Tao Wu
AU  - Saeho Chong
TI  - <strong>Nonclinical Pharmacokinetics and ADME of Givosiran, the First Approved GalNAc-conjugated RNAi Therapeutic</strong>
AID  - 10.1124/dmd.121.000381
DP  - 2021 Jan 01
TA  - Drug Metabolism and Disposition
PG  - DMD-AR-2021-000381
4099  - http://dmd.aspetjournals.org/content/early/2021/05/03/dmd.121.000381.short
4100  - http://dmd.aspetjournals.org/content/early/2021/05/03/dmd.121.000381.full
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.