Influence of Charge, Hydrophobicity, and Size on Vitreous Pharmacokinetics of Large Molecules.

Autor: Crowell SR; Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, South San Francisco, CA, USA., Wang K; Drug Delivery, Genentech, South San Francisco, CA, USA., Famili A; Drug Delivery, Genentech, South San Francisco, CA, USA., Shatz W; Protein Chemistry, Genentech, South San Francisco, CA, USA., Loyet KM; Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA, USA., Chang V; Bioanalytical Sciences, Genentech, South San Francisco, CA, USA., Liu Y; Bioanalytical Sciences, Genentech, South San Francisco, CA, USA., Prabhu S; Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, South San Francisco, CA, USA., Kamath AV; Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, South San Francisco, CA, USA., Kelley RF; Drug Delivery, Genentech, South San Francisco, CA, USA.
Jazyk: angličtina
Zdroj: Translational vision science & technology [Transl Vis Sci Technol] 2019 Nov 01; Vol. 8 (6), pp. 1. Date of Electronic Publication: 2019 Nov 01 (Print Publication: 2019).
DOI: 10.1167/tvst.8.6.1
Abstrakt: Purpose: Development of therapeutics for retinal disease with improved durability is hampered by inadequate understanding of pharmacokinetic (PK) drivers following intravitreal injection. Previous work shows that hydrodynamic radius is correlated with vitreal half-life over the range of 3 to 7 nm, and that charge and hydrophobicity influence systemic clearance. Better understanding the molecular attributes affecting vitreal elimination half-life enables improved design of therapeutics and enhances clinical translatability.
Methods: Impacts of charge and hydrophobicity on vitreal PK in the rabbit were systematically assessed using antibody and antibody fragment (Fab) variant series, including ranibizumab, altered through amino acid changes in hypervariable regions of the light chain. The impact of molecule size on vitreal PK was assessed in the rabbit, nonhuman primate, and human for a range of molecules (1-45 nm, net charge -1324 to +22.9 in rabbit), including published and internal data.
Results: No correlation was observed between vitreal PK and charge or hydrophobicity. Equivalent rabbit vitreal PK was observed for ranibizumab and its variants with isoelectric points (pI) in the range of 6.8 to 10.2, and hydrophobicities of the variable domain unit (FvHI) between 1009 and 1296; additional variant series had vitreal PK similarly unaffected by pI (5.4-10.2) and FvHI (1004-1358). Strong correlations were observed between vitreal half-life and hydrodynamic radius for preclinical species ( R 2 = 0.8794-0.9366).
Conclusions: Diffusive properties of soluble large molecules, as quantified by hydrodynamic radius, make a key contribution to vitreal elimination, whereas differences in charge or hydrophobicity make minor or negligible contributions.
Translational Relevance: These results support estimation of vitreal elimination rates based on molecular size in relevant preclinical species and humans.
(Copyright 2019 The Authors.)
Databáze: MEDLINE