Abstract
Evaluation of species differences and systemic exposure multiples (or ratios) in toxicological animal species versus human is an ongoing exercise during the course of drug development. The systemic exposure ratios are best estimated by directly comparing area under the plasma concentration-time curves (AUCs), and sometimes by comparing the dose administered, with the dose being adjusted either by body surface area (BSA) or body weight (BW). In this study, the association between AUC ratio and the administered dose ratio from animals to human were studied using a retrospective data-driven approach. The dataset included nine antisense oligonucleotides (ASOs) with 2′-O-(2-methoxyethyl) modifications, evaluated in two animal species (mouse and monkey) following single and repeated parenteral administrations. We found that plasma AUCs were similar between ASOs within the same species, and are predictable to human exposure using a single animal species, either mouse or monkey. Between monkey and human, the plasma exposure ratio can be predicted directly based on BW-adjusted dose ratios, whereas between mouse and human, the exposure ratio would be nearly fivefold lower in mouse compared to human based on BW-adjusted dose values. Thus, multiplying a factor of 5 for the mouse BW-adjusted dose would likely provide a reasonable AUC exposure estimate in human at steady-state.
Highlights
Antisense oligonucleotides (ASOs) with 2′-O-(2-methoxyethyl) (2′-MOE) (Figure 1), represent a platform of RNA-based therapeutics designed to hybridize to their target RNA via Watson-Crick base pairing and prevent expression of the encoded “disease-related” protein product
Pharmacokinetic properties of ASOs The primary route of administration for oligonucleotides for systemic applications is by parenteral injection, either intravenous (i.v.) infusion or subcutaneous (s.c.) injection
Following systemic s.c. or i.v. administration, plasma ASO concentrations rapidly declined from peak concentrations in a multiexponential fashion as characterized by a dominant initial rapid distribution phase representing extensive distribution to tissues, followed by a much slower terminal elimination phase in both animals and humans as reported previously.[11,12,14]
Summary
Antisense oligonucleotides (ASOs) with 2′-O-(2-methoxyethyl) (2′-MOE) (Figure 1), represent a platform of RNA-based therapeutics designed to hybridize to their target RNA via Watson-Crick base pairing and prevent expression of the encoded “disease-related” protein product. Determination of systemic (plasma) exposure ratios in toxicological animal species versus humans are best done by comparing area under the plasma concentration-time curve (AUC) values. Such exposure ratios are commonly used to relate the exposure achieved in animal pharmacology or toxicology studies to human and facilitate the assessment of the relevance of these findings to clinical efficacy or safety.[10] For example, determination of the “margin of safety” or “margin of exposure” is typically done based on the plasma AUC ratio of the no observable adverse effect level (NOAEL)
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