Lumasiran: Clinical Pharmacology

      The absorption, distribution, metabolism, and excretion properties of lumasiran in human were evaluated based on PK data from lumasiran clinical studies and supplemented with nonclinical PK studies in rats and monkeys. A human radiolabeled ADME study was not conducted with lumasiran given its long half-life in the liver tissue and potential health hazard to healthy volunteers from prolonged exposure to radiation.1,2

o        Lumasiran is rapidly absorbed following SC administration into the plasma, with a median (range) Tmax of 4 (0.15 to 12) hours.2,3

o        Lumasiran primarily distributes to the liver through ASGPR-mediated hepatic uptake after SC administration. Plasma protein binding ranges from 77 to 85% at clinically relevant concentrations. Based on nonclinical data, the estimated Vd/F is 4.9 L (0.07 L/kg).1,2

o        Lumasiran is metabolized by endo- and exonucleases to oligonucleotides of shorter lengths.3

o        Renal excretion is a minor pathway of elimination for lumasiran. Less than 26% of the administered dose of lumasiran is excreted unchanged into the urine within 24 hours.2,3

      Plasma concentrations of lumasiran do not reflect the extent or duration of the PD activity of lumasiran. Rapid and targeted uptake of lumasiran by the liver results in rapid decline in plasma concentrations. In the combined analysis of adult healthy subjects and pediatric and adult patients with PH1 across studies, the mean terminal plasma half-life following a single SC dose of lumasiran was 5.2 hours. Lumasiran concentrations were below LLoQ and not detectable in the plasma after 48 hours.1,2

      Based on nonclinical studies, PK/PD modeling predicted a lumasiran terminal half-life in human liver to be 66.9 days. In the liver, lumasiran exhibits a long half-life leading to maintenance of PD effect over the monthly or quarterly dosing interval.1,2