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Research ArticleArticle

Nonclinical Pharmacokinetics and Absorption, Distribution, Metabolism, and Excretion of Givosiran, the First Approved N-Acetylgalactosamine–Conjugated RNA Interference Therapeutic

Jing Li, Ju Liu, Xuemei Zhang, Valerie Clausen, Chris Tran, Michael Arciprete, Qianfan Wang, Carrie Rocca, Li-Hua Guan, Guodong Zhang, Diana Najarian, Yuanxin Xu, Peter Smith, Jing-Tao Wu and Saeho Chong
Drug Metabolism and Disposition July 2021, 49 (7) 572-580; DOI: https://doi.org/10.1124/dmd.121.000381
Jing Li
Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts
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Ju Liu
Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts
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Xuemei Zhang
Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts
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Valerie Clausen
Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts
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Chris Tran
Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts
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Michael Arciprete
Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts
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Qianfan Wang
Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts
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Carrie Rocca
Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts
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Li-Hua Guan
Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts
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Guodong Zhang
Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts
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Diana Najarian
Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts
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Yuanxin Xu
Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts
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Peter Smith
Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts
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Jing-Tao Wu
Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts
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Saeho Chong
Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts
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Abstract

Givosiran is an N-acetylgalactosamine–conjugated RNA interference therapeutic that targets 5′-aminolevulinate synthase 1 mRNA in the liver and is currently marketed for the treatment of acute hepatic porphyria. Herein, nonclinical pharmacokinetics and absorption, distribution, metabolism, and excretion properties of givosiran were characterized. Givosiran was completely absorbed after subcutaneous administration with relatively short plasma elimination half-life (t1/2; less than 4 hours). Plasma exposure increased approximately dose proportionally with no accumulation after repeat doses. Plasma protein binding 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–mediated uptake, and the t1/2 in the liver was significantly longer (∼1 week). Givosiran was metabolized by nucleases, not cytochrome P450 (P450) isozymes, across species with no human unique metabolites. Givosiran metabolized to form one primary active metabolite with the loss of one nucleotide from the 3′ end of antisense strand, AS(N-1)3′ 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 P450 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 P450 isozymes and drug transporters.

SIGNIFICANCE STATEMENT Nonclinical pharmacokinetics and absorption, distribution, metabolism, and excretion (ADME) properties of givosiran were characterized. Givosiran shows similar pharmacokinetics and ADME properties across rats and monkeys in vivo and across human and animal matrices in vitro. Subcutaneous 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 acute hepatic porphyria.

Footnotes

    • Received January 19, 2021.
    • Accepted April 19, 2021.
  • This work was supported by Alnylam Pharmaceuticals Inc. The authors are, or were during the time this work was conducted, employees and stockholders of Alnylam Pharmaceuticals.

  • https://dx.doi.org/10.1124/dmd.120.000381.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (7)
Drug Metabolism and Disposition
Vol. 49, Issue 7
1 Jul 2021
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Research ArticleArticle

Nonclinical PK and ADME of Givosiran

Jing Li, Ju Liu, Xuemei Zhang, Valerie Clausen, Chris Tran, Michael Arciprete, Qianfan Wang, Carrie Rocca, Li-Hua Guan, Guodong Zhang, Diana Najarian, Yuanxin Xu, Peter Smith, Jing-Tao Wu and Saeho Chong
Drug Metabolism and Disposition July 1, 2021, 49 (7) 572-580; DOI: https://doi.org/10.1124/dmd.121.000381

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Research ArticleArticle

Nonclinical PK and ADME of Givosiran

Jing Li, Ju Liu, Xuemei Zhang, Valerie Clausen, Chris Tran, Michael Arciprete, Qianfan Wang, Carrie Rocca, Li-Hua Guan, Guodong Zhang, Diana Najarian, Yuanxin Xu, Peter Smith, Jing-Tao Wu and Saeho Chong
Drug Metabolism and Disposition July 1, 2021, 49 (7) 572-580; DOI: https://doi.org/10.1124/dmd.121.000381
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