Predictive dose-based estimation of systemic exposure multiples in mouse and monkey relative to human for antisense...

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Toxicology
• Drug Development

Background:

• Accurate prediction of human systemic exposure from animal models is crucial in drug development.
• Systemic exposure ratios are typically estimated using area under the plasma concentration-time curves (AUCs) or dose adjustments by body surface area (BSA) or body weight (BW).

Purpose of the Study:

• To investigate the association between area under the plasma concentration-time curve (AUC) ratios and administered dose ratios from animals to humans for antisense oligonucleotides (ASOs).
• To determine the predictability of human exposure using data from mouse and monkey models.

Main Methods:

• A retrospective data-driven approach was employed.
• The dataset comprised nine 2'-O-(2-methoxyethyl) modified antisense oligonucleotides (ASOs).
• Data from single and repeated parenteral administrations in mouse and monkey models were analyzed.

Main Results:

• Plasma AUCs for ASOs were consistent within the same animal species.
• Human exposure to ASOs could be predicted using either mouse or monkey data.
• Monkey to human plasma exposure ratios correlated directly with BW-adjusted dose ratios.
• Mouse to human exposure ratios were approximately fivefold lower than expected based on BW-adjusted doses.

Conclusions:

• A BW-adjusted dose ratio from monkeys can predict human exposure for ASOs.
• Multiplying the mouse BW-adjusted dose ratio by a factor of 5 may provide a reasonable AUC exposure estimate in humans at steady-state.
• This finding aids in refining preclinical to clinical exposure predictions for ASO therapeutics.