Development of a population pharmacokinetic/pharmacodynamic model of lepodisiran, a small interfering RNA targeting lipoprotein(a), in healthy adults

How was the population pharmacokinetic (PK)/pharmacodynamic (PD) (pop-PK/PD) model of lepodisiran, a small interfering RNA targeting lipoprotein(a) (Lp(a)), in healthy adults developed?

Methods: The study involved 48 participants who received a single subcutaneous dose of lepodisiran at various doses or a placebo. Serial plasma samples were collected up to 24 hours after administration and on specific days throughout the study period. Lp(a) measurements were taken regularly to evaluate the long-term effects of the drug. A compartmental PK model was developed to describe the drug's distribution, and different absorption models were tested. A liver compartment was added to account for the temporal difference between plasma concentrations and drug response. The liver volume was calculated based on individual body surface area. The modeling was done using NONMEM v7.5.0 with FOCE-I.

Results: The one-compartment PK model adequately described lepodisiran plasma PK. Body weight was found to be a covariate on the volume of distribution. Maximal concentrations and time to achieve maximal concentrations varied greatly between subjects. A combined zero- and first-order absorption model was used to account for this variability. Inter-individual variabilities were estimated for absorption rate, clearance, and volume of distribution parameters. Lepodisiran was rapidly absorbed into the liver but slowly eliminated. A clear exposure-response relationship was established, with significant Lp(a) knockdown (KD) observed at doses above 12 mg. Higher doses resulted in greater and more durable Lp(a) reduction.

Conclusion: A pop-PK/PD model was developed using phase 1 data from healthy adults with elevated Lp(a) which robustly explained the time course of lepodisiran plasma concentrations and Lp(a) levels. The inclusion of the liver compartment based on the mechanistic understanding of GalNAc-siRNAs enabled characterization of the temporal difference between short-lived plasma exposure and prolonged effect on Lp(a) lowering. Lepodisiran demonstrated durable and significant Lp(a) KD at doses greater than 96 mg. Results from this modelling suggest the potential to dose once or twice per year; these dosing regimens are being assessed in the lepodisiran ALPACA phase 2 trial (NCT05565742).

Publication History

Article published online:
28 May 2025