(M-086) Model-Based Evaluation of Lumasiran Plasma and Liver Pharmacokinetics in Non-Human Primates

Heajin Jun – Clinical Pharmacology & Pharmacometrics – Alnylam Pharmaceuticals; Wansu Park – Clinical Pharmacology & Pharmacometrics – Alnylam Pharmaceuticals; Hyun Gi Yun – Clinical Pharmacology & Pharmacometrics – Alnylam Pharmaceuticals; Jongtae Lee – Clinical Pharmacology & Pharmacometrics – Alnylam Pharmaceuticals; Nitin Mehrotra – Clinical Pharmacology & Pharmacometrics – Alnylam Pharmaceuticals; Gabriel Robbie – Clinical Pharmacology & Pharmacometrics – Alnylam Pharmaceuticals

Objectives: The primary objective of this study is to comprehensively elucidate the pharmacokinetic (PK) characteristics of lumasiran in non-human primates (NHPs), including flip-flop kinetics, saturable hepatic uptake, and fraction excreted in urine. It also aims to bridge the gap between transient plasma PK and prolonged pharmacodynamic (PD) responses by incorporating delayed PK in the liver, the target organ of lumasiran. Finally, these findings will be utilized to predict and interpret plasma PK in humans.

Methods: The nonclinical PK model integrated plasma and liver concentrations of lumasiran in NHPs following single or multiple, intravenous (IV) or subcutaneous (SC) administration, obtained from three PK and toxicokinetic studies. The model was developed using a first-order conditional estimation method with interaction in NONMEM (version 7.5.0). External validation with the data from healthy adults (NCT02706886) was conducted based on allometric scaling, whereas for patients with primary hyperoxaluria type 1 (PH1) and renal impairment (NCT04152200), it also included a sensitivity test accounting for adjustments in renal clearance.

Results: A total of 1282 plasma (dose range: 0.1-300 mg/kg) and 159 liver (0.1-10 mg/kg) measurements from 106 NHPs were included in the final model. Plasma PK was best described by a two-compartment model with first-order absorption. The estimated absorption rate constant was slower than the beta-phase rate constant, confirming flip-flop kinetics. A one-compartment model best described the liver PK, with a prolonged terminal half-life compared to that in plasma. To account for the saturation of asialoglycoprotein receptor-mediated hepatic uptake at higher plasma concentrations, a Michaelis-Menten equation was applied to a rapid hepatic uptake pathway. The Michaelis-Menten constant (Km) was equivalent to the amount in depot immediately after SC dosing at ~20 mg/kg in NHPs. The model predicted that approximately 20% of the administered dose (≤10 mg/kg) was excreted in urine, which aligns with observed data. The model predicted plasma concentrations are aligned with the observed PK data in healthy adults, as well as patients with PH1 and advanced kidney disease.

Conclusions: The novel, comprehensive model simultaneously describing plasma and liver concentrations of lumasiran following IV or SC administration was successfully developed and validated with clinical data. This research lays a strong foundation for interpreting PD responses by elucidating the relationship between plasma and liver PK, with potential applications for other liver-targeting siRNA therapies.

Citations: [1] Frishberg Y, Deschênes G, Groothoff JW, et al. Phase 1/2 Study of Lumasiran for Treatment of Primary Hyperoxaluria Type 1: A Placebo-Controlled Randomized Clinical Trial. Clin J Am Soc Nephrol. 2021;16(7):1025-1036. doi:10.2215/CJN.14730920
[2] Michael M, Groothoff JW, Shasha-Lavsky H, et al. Lumasiran for Advanced Primary Hyperoxaluria Type 1: Phase 3 ILLUMINATE-C Trial. Am J Kidney Dis. 2023;81(2):145-155.e1. doi:10.1053/j.ajkd.2022.05.012

Keywords: Lumasiran, Plasma and Liver, Pharmacokinetic