Translational pharmacokinetic/pharmacodynamic model for mRNA-0184, an investigational therapeutic for the treatment of heart failure.
Clin Transl Sci
; 17(8): e13894, 2024 Aug.
Article
en En
| MEDLINE
| ID: mdl-39072952
ABSTRACT
Heart failure (HF) is a complex, progressive disorder that is associated with substantial morbidity and mortality on a global scale. Relaxin-2 is a naturally occurring hormone that may have potential therapeutic benefit for patients with HF. To investigate the therapeutic potential of relaxin in the treatment of patients with HF, mRNA-0184, a novel, investigational, lipid nanoparticle (LNP)-encapsulated mRNA therapy that encodes for human relaxin-2 fused to variable light chain kappa (Rel2-vlk) was developed. A translational semi-mechanistic population pharmacokinetic (PK)/pharmacodynamic (PD) model was developed using data from non-human primates at dose levels ranging from 0.15 to 1 mg/kg. The PK/PD model was able to describe the PK of Rel2-vlk mRNA and translated Rel2-vlk protein in non-human primates adequately with relatively precise estimates. The preclinical PK/PD model was then scaled allometrically to determine the human mRNA-0184 dose that would achieve therapeutic levels of Rel2-vlk protein expression in patients with stable HF with reduced ejection fraction. Model-based simulations derived from the scaled PK/PD model support the selection of 0.025 mg/kg as an appropriate starting human dose of mRNA-0184 to achieve average trough relaxin levels between 1 and 2.5 ng/mL, which is the potential exposure for cardioprotective action of relaxin.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Relaxina
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ARN Mensajero
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Insuficiencia Cardíaca
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Clin Transl Sci
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos