Pharmacokinetics and Pharmacodynamics of the Small Interfering Ribonucleic Acid, Givosiran, in Patients With Acute Hepatic Porphyria

• Published in: Clinical pharmacology and therapeutics Vol. 108; no. 1; p. 63
• Main Authors: Agarwal, Sagar, Simon, Amy R, Goel, Varun, Habtemariam, Bahru A, Clausen, Valerie A, Kim, Jae B, Robbie, Gabriel J
• Format: Journal Article
• Language: English
• Published: United States 01.07.2020
• Subjects: Acetylgalactosamine - administration & dosage; Acetylgalactosamine - analogs & derivatives; Acetylgalactosamine - pharmacokinetics; Acetylgalactosamine - pharmacology; Adult; Aminolevulinic Acid - urine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Half-Life; Humans; Injections, Subcutaneous; Male; Middle Aged; Porphobilinogen - urine; Porphyria, Acute Intermittent - drug therapy; Pyrrolidines - administration & dosage; Pyrrolidines - pharmacokinetics; Pyrrolidines - pharmacology; Young Adult
• ISSN: 1532-6535
• DOI: 10.1002/cpt.1802

Givosiran is a small interfering ribonucleic acid agent that was recently approved in the United States for the treatment of acute hepatic porphyria (AHP). This phase I study evaluated the safety, pharmacokinetic, and pharmacodynamic profile of subcutaneously (SC) administered givosiran in patients with acute intermittent porphyria, the most common AHP type. Givosiran was rapidly absorbed from the SC injection site with peak plasma concentrations achieved within 0.5-5 hours followed by elimination with a short half-life of 4-10 hours. Plasma exposures of AS(N-1)3' givosiran, an active metabolite with equal potency as givosiran, was 35%-75%. Givosiran treatment resulted in a rapid and dose-dependent reduction in urinary aminolevulinic acid (ALA) and porphobilinogen (PBG) towards the upper limit of normal (ULN) in AHP patients. Greater and more sustained reductions in ALA and PBG were achieved with once monthly dosing compared with once quarterly dosing. After monthly dosing, trough ALA levels were reduced to below the ULN, approximately 95% reduction from baseline, at both the 2.5 and 5.0 mg/kg doses.