Meta-Analysis of the Ocular Half-Life (T½) of Fabs and IgGs in Humans and Other Species: Two Ways that Size Matters

Abstract

Purpose : Fab fragments and IgG antibodies are injected intravitreally to treat retinal diseases. Their duration of target suppression is related to their ocular T½ [1]. To assess the effect of molecular size (hydrodynamic radius, Rh) on T½ we conducted a meta-analysis of published and unpublished data derived from diffusion coefficients (D) and molecular models, and from ocular pharmacokinetic (PK) studies in humans and other species. The effect of vitreal size on T½ was also assessed.

Methods : Experimental estimates of Rh for Fabs and IgGs were calculated from D values using the Stokes-Einstein equation; theoretical estimates were based on molecular weights and structure models. Ocular T½ values were derived from PK studies in the rat, rabbit, cynomolgus and rhesus monkeys, minipig and humans. Literature data on the vitreal volume (V_vit) were used to compute the vitreal radius (r_vit) and vitreal diffusion time (T_{vit, diff}), i.e. time to diffuse from the center to the surface of the vitreal globe, as given in [1].

Results : Table 1 summarizes the available Rh and T½ data for Fab and IgG molecules in the six species. Rh and T½ values are significantly greater for IgGs than Fabs. T½ values tend to increase with r_vit across species. According to [1], T½ should be proportional to T_{vit, diff}, which implies a proportionality to both Rh and r_vit². The proportionality to Rh is demonstrated by the similar ratios (IgG-to-Fab) of Rh (1.7) and T½, which varies from 1.3 to 1.8 across species. The proportionality to r_vit² is confirmed in Figure 1, which plots T½ vs. T_{vit, diff} for all molecules and species. The regression line, with a slope of 3.06, is highly significant (P<0.001). In humans, the mean T½ values for Fabs (6.5 days) and IgGs (8.9 days) fall close to the line.

Conclusions : A meta-analysis of ocular T½ data for Fabs and IgGs in humans and other species, shows that “size matters” in two distinct ways. T½ values increase with molecular size (Rh) and also with the radial size of the vitreal globe. These findings are consistent with a diffusion-controlled process for drug elimination from the vitreous [1].

[1] Hutton-Smith et al. Mol Pharm 2016;13:2941-2950

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

 

Table 1: Rh and T½ values for Fabs and IgGs in six species. V_vit and r_vit also given.

 

Figure 1: Regression plot of T½ values vs. vitreal diffusion times. Shaded area is 95% confidence interval.