Titre du document / Document title

Pharmacokinetics and safety of an anti-vascular endothelial growth factor aptamer (NX1838) following injection into the vitreous humor of rhesus monkeys

Auteur(s) / Author(s)

DROLET Daniel W. ⁽¹⁾ ; NELSON Joyce ⁽²⁾ ; TUCKER Christopher E. ⁽¹⁾ ; ZACK Philip M. ⁽¹⁾ ; NIXON Kerry ⁽²⁾ ; BOLIN Richard ⁽¹⁾ ; JUDKINS Mark B. ⁽²⁾ ; FARMER James A. ⁽²⁾ ; WOLF Julie L. ⁽¹⁾ ; GILL Stanley C. ⁽¹⁾ ; BENDELE Raymond A. ⁽¹⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Gilead Sciences Inc., 2860 Wilderness Place, Boulder, CO 80301, ETATS-UNIS
⁽²⁾ Sierra Biomedical, 587 Dunn Circle, Sparks, NV 89431, ETATS-UNIS

Résumé / Abstract

Purpose. The objective of this study was to determine the pharmacokinetics and safety for NX1838 following injection into the vitreous humor of rhesus monkeys. Methods. Plasma and vitreous humor pharmacokinetics were determined following a single bilateral 0.25, 0.50, 1.0, 1.5, or 2.0 mg/eye dose. In addition, the pharmacokinetics and toxicological properties of NX1838 were determined following six biweekly bilateral injections of 0.25 or 0.50 mg/eye or following four biweekly bilateral injections of 0.10 mg per eye followed by two biweekly bilateral injections of 1.0 mg per eye. Results. Plasma and vitreous humor NX1838 concentrations were linearly related to the dose administered. NX1838 was cleared intact from the vitreous humor into the plasma with a half-life of approximately 94 h, which was in agreement with the plasma terminal half-life. Vascular endothelial growth factor (VEGF)-binding assays demonstrated that the NX1838 remaining in the vitreous humor after 28 days was fully active. No toxicological effects or antibody responses were evident. Conclusions. The no observable effect level was greater than six biweekly bilateral 0.50 mg/eye doses or two biweekly bilateral 1.0 mg/eye doses. These pharmacokinetic and safety data support monthly I or 2 mg/eye dose regimens in human clinical trials.

Revue / Journal Title

Pharmaceutical research   ISSN 0724-8741   CODEN PHREEB 

Source / Source

2000, vol. 17, n^o12, pp. 1503-1510 (24 ref.)

Langue / Language

Anglais

Editeur / Publisher

Springer, New York, NY, ETATS-UNIS  (1984) (Revue)

Mots-clés anglais / English Keywords

Vascular endothelium growth factor ; Oligonucleotide ; Protein inhibitor ; Vitreous body ; Eye ; Intraocular administration ; Monkey ; Animal ; Pharmacokinetics ; Toxicity ; Blood plasma ; Single dose ; Absorption ; Multiple dose ; Primates ; Mammalia ; Vertebrata ;

Mots-clés français / French Keywords

Facteur croissance endothélium vasculaire ; Oligonucléotide ; Inhibiteur protéique ; Corps vitré ; Oeil ; Voie intraoculaire ; Singe ; Animal ; Pharmacocinétique ; Toxicité ; Plasma sanguin ; Dose unique ; Absorption ; Dose répétée ; NX 1838 ; Primates ; Mammalia ; Vertebrata ;

Mots-clés espagnols / Spanish Keywords

Factor crecimiento endotelio vascular ; Oligonucleótido ; Inhibidor proteico ; Cuerpo vidrioso ; Ojo ; Vía intraocular ; Mono ; Animal ; Farmacocinética ; Toxicidad ; Plasma sanguíneo ; Dosis única ; Absorción ; Dosis múltiple ; Primates ; Mammalia ; Vertebrata ;

Localisation / Location

INIST-CNRS, Cote INIST : 20257, 35400009872509.0090