Long-Acting Poly(ADP-ribose) Polymerase Inhibitor Prodrug for Humans.
Bioconjug Chem
; 35(4): 551-558, 2024 Apr 17.
Article
en En
| MEDLINE
| ID: mdl-38591781
ABSTRACT
Poly(ADP-ribose) polymerase inhibitors (PARPi) have been approved for once or twice daily oral use in the treatment of cancers with BRCA defects. However, for some patients, oral administration of PARPi may be impractical or intolerable, and a long-acting injectable formulation is desirable. We recently developed a long-acting PEGylated PARPi prodrug, PEGâ¼talazoparib (TLZ), which suppressed the growth of PARPi-sensitive tumors in mice for very long periods. However, the release rate of TLZ from the conjugate was too fast to be optimal in humans. We prepared several new PEGâ¼TLZ prodrugs having longer half-lives of drug release and accurately measured their pharmacokinetics in the rat. Using the rates of release of TLZ from these prodrugs and the known pharmacokinetics of free TLZ in humans, we simulated the pharmacokinetics of the macromolecular prodrugs and released TLZ in humans. From several possibilities, we chose two conjugates that could be administered intravenously every 2 weeks and maintain TLZ within its known therapeutic window. We describe situations where the PEGâ¼TLZ conjugates would find utility in humans and suggest how the intravenously administered long-acting prodrugs could in fact be more effective than daily oral administration of free TLZ.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Profármacos
/
Neoplasias
/
Antineoplásicos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Bioconjug Chem
Asunto de la revista:
BIOQUIMICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos