Pharmacokinetics and Safety of an Intravitreal Humanized Anti-VEGF-A Monoclonal Antibody

• Published in: Journal of experimental pharmacology 2021-05, Vol.13, p.545
• Main Authors: Quintana-Hau, Juan D, Quinonez-Alvarado, Mayra G, Olvera-Montano, Oscar, Sanchez-Rios, Alejandra, Baiza-Duran, Leopoldo, Munoz-Villegas, Patricia
• Format: Article
• Language: English
• Subjects: Monoclonal antibodies; Vascular endothelial growth factor
• ISSN: 1179-1454; 1179-1454

Background: PRO-169 is a biosimilar candidate to bevacizumab (BEV), a monoclonal antibody (mAb) that inhibits vascular endothelial growth factor-A (VEGF-A) developed for intravitreal use. The current study demonstrates the intraocular pharmacokinetics (PK) of PRO-169 and its safety using New Zealand white (NZW) rabbits. Methods: Intraocular concentration was evaluated in thirty-six rabbits at 1h, 1, 2, 5, 14 and 30 days after a single bilateral injection of PRO-169 or BEV (1.25 mg/0.05 mL). In a secondary experiment, safety was evaluated after three consecutive unilateral injections at 30-day intervals in twenty-four rabbits (PRO-169: 1.25 mg/0.05 mL or ranibizumab [RZB]: 0.5 mg/0.05 mL), by liver-associated enzymes (LAE), ophthalmological examination and adverse event (AE) incidence. Primary endpoints were vitreous maximum concentration ([C.sub.max]), time to attain maximum concentration ([t.sub.max]), area under curve ([AUC.sub.0-t]), half-life ([t.sub.1/2]) and LAE. Secondary endpoints included aqueous humor (AH) and plasma pharmacokinetics, clinical examination and AEs. Results: The [C.sub.max] in the vitreous was 593.75 [+ or -] 45.63 (PRO-169) vs 644.79 [+ or -] 62.65 [micro]g/mL (BEV) (p= 0.136). [T.sub.max] was 0.53 [+ or -] 0.82 vs 0.85 [+ or -] 0.73 days (p= 0.330). The [AUC.sub.0-t] was 3837.72 [+ or -] 465.91 vs 4247.31 [+ or -] 93.99 days*[micro]g/mL (p= 0.052) and the half-life was 4.99 [+ or -] 0.89 vs 5.18 [+ or -] 0.88 days (p= 0.711). LAEs were normal in 92% of NZW rabbits; no differences between groups were observed (p>0.05). The AH and plasma PKs were also similar. Finally, clinical examinations found no alterations. AEs were observed in 25% of PRO-169 rabbits, without differences vs RZB (p=0.399). Conclusion: PRO-169 can be efficiently diffused and distributed in ocular compartments, showing vitreous pharmacokinetics analogous to BEV. The safety experiment did not find evidence of clinical alterations from a repeated injection of PRO-169. These results provide scientific justification supporting that PRO-169 should be evaluated in future clinical trials to confirm its safety and efficacy. Keywords: bevacizumab, pharmacokinetics, ranibizumab, safety, vascular endothelial growth factor