Multispecies minimal physiologically based pharmacokinetic-pharmacodynamic model of antisense oligonucleotides for...

Antisense oligonucleotides (ASOs) are selective small biological drugs used to decrease targeted proteins by suppressing mRNA expression. In this study, a quantitative framework was developed to characterize the disposition and effects of such drugs in the central nervous system across species to facilitate the translation of preclinical pharmacology to the clinic. A minimal physiologically based pharmacokinetic (PK)-pharmacodynamic (PD) model for ASOs was developed using published drug and species-specific physiological information, including PK of nusinersen and preclinical PK and mRNA expression for an investigational compound targeting glutamate receptor subunit 1. The model describes relevant pharmacological processes, including (1) clathrin-dependent/independent endocytosis, (2) exocytosis, (3) exonuclease metabolism, (4) macropinocytosis, and (5) knockdown of the targeted protein. Most physiological values were obtained from literature, and drug-specific parameters were estimated. The model captured PK data in preclinical species (mice, rats, and monkeys), infants, and pediatric subjects from phase 1 and 2 studies. Renal clearances were fixed to 2.07, 25.2, 170.7, and 405 mL/h for mice, rats, monkeys, and humans, which were based on prior published values for oligonucleotides. Glutamate receptor subunit 1 mRNA and protein expression in rats were well characterized using a precursor-dependent indirect response model assuming maximal inhibition (I_max) set to 1. Overall, the biodistribution of 2 ASOs across species were characterized by implementing allometric scaling and minimal physiologically based PK concepts. The final model provides insights into the role of specific disposition processes in controlling ASO PK-PD properties in the central nervous system. SIGNIFICANCE STATEMENT: Antisense oligonucleotides enable central nervous system-targeted gene therapy and precision medicine. Using a translational multispecies minimal physiologically based PK-PD model, drug- and system-specific factors were identified that influence the biodistribution of antisense oligonucleotides in preclinical species and humans. The final model can readily translate preclinical data to anticipate human drug exposures in the brain and plasma, help in lead and backup compound selection, project first-in-human dose levels, interpret early human PK-PD data, and facilitate the identification of recommended phase 2 doses.