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Pharmacokinetics of Patisiran, the First Approved RNA Interference Therapy in Patients With Hereditary Transthyretin-Mediated Amyloidosis.


ABSTRACT: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, inherited, progressively debilitating, and often fatal disease caused by deposition of mutated transthyretin (TTR) protein. Patisiran is an RNA interference therapeutic comprising a novel small interfering ribonucleic acid (ALN-18328) formulated with 2 novel lipid excipients, DLin-MC3-DMA and PEG2000 -C-DMG, in a lipid nanoparticle targeted to inhibit hepatic TTR synthesis. Here we report the pharmacokinetics (PK) of ALN-18328, DLin-MC3-DMA, and PEG2000 -C-DMG from a phase 2 multiple-ascending-dose study and its open-label extension (OLE) in patients with hATTR amyloidosis. Twenty-nine patients received 2 intravenous infusions of patisiran of 0.01, 0.05, 0.15, or 0.3 mg/kg at 3- or 4-week intervals; of these, 27 patients received 0.3 mg/kg once every 3 weeks over 24 months in the OLE study. Plasma PK profiles of ALN-18328 and DLin-MC3-DMA exhibited 2 phases, the first characterized by a short distribution half-life and the second by a minor peak and relatively long terminal elimination half-life. PK exposures to 3 analytes increased proportionally across the dose range of 0.01 to 0.3 mg/kg. For ALN-18328, mean terminal elimination half-life was 3.2 days, mean total clearance was 3.0 mL/h/kg, and urinary excretion was negligible. All 3 analytes exhibited stable PK profiles with chronic dosing over 2 years. The 2- to 3-fold plasma accumulation (AUC? ) of ALN-18328 at steady state is attributable to the association of ALN-18328 with the cationic lipid DLin-MC3-DMA. There was no appreciable accumulation of PEG2000 -C-DMG.

SUBMITTER: Zhang X 

PROVIDER: S-EPMC7187331 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Pharmacokinetics of Patisiran, the First Approved RNA Interference Therapy in Patients With Hereditary Transthyretin-Mediated Amyloidosis.

Zhang Xiaoping X   Goel Varun V   Robbie Gabriel J GJ  

Journal of clinical pharmacology 20191127 5


Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, inherited, progressively debilitating, and often fatal disease caused by deposition of mutated transthyretin (TTR) protein. Patisiran is an RNA interference therapeutic comprising a novel small interfering ribonucleic acid (ALN-18328) formulated with 2 novel lipid excipients, DLin-MC3-DMA and PEG<sub>2000</sub> -C-DMG, in a lipid nanoparticle targeted to inhibit hepatic TTR synthesis. Here we report the pharmacokinetics (PK) of ALN  ...[more]

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