Pharmacokinetics of intravitreal glial cell line-derived neurotrophic factor: Experimental studies in pigs

The purpose of this study was to establish the intravitreal (ITV) pharmacokinetics of glial cell line-derived neurotrophic factor (GDNF) and observe possible complications after ITV injection. Twenty Danish landrace pigs and 34 eyes were included in the study; 30 were injected with 100 ng of GDNF, two controls were injected without GDNF, and two received no injection. At post-injection time points of 1, 2, 3, 6 hours (h), 1, 2, 4 or 7 days (d) eyes were enucleated and the ITV concentration of GDNF (cGDNF) was determined by enzyme-linked immunosorbent assay, and activity was tested using a retinal ganglion cell line (RGC5) bioassay. Indirect ophthalmoscopy, intraocular pressure assessment, and fundus photography were performed before enucleation. There was initial variability in the cGDNF, but after 24 h GDNF was cleared in a monoexponential fashion with a half-life of 37 h (CL 33–43 h). Therapeutic concentrations were present for 15 d (CL 13–18 d) when an extrapolation was done. GDNF-injected vitreous samples stimulated increased survival of RGC5s at 24 h post-delivery (p = 0.002) compared with no-GDNF vitreous controls. This effect was independent of intraocular incubation time when cGDNF was normalized to 5 ng/ml. A semi-logarithmic dose–response curve showed linearity between 0.1 and 10 ng/ml. None of the eyes showed any signs of inflammation or other complications. A single ITV GDNF injection of 100 ng leads to therapeutic levels for 15 days in the porcine eye. The GDNF was stable in the intraocular environment and no adverse events were observed. GDNF might therefore play a role in the future treatment of acute retinal damage.

Research highlights
► First description of intravitreal pharmacokinetics of GDNF: Monoexponential decay of GDNF from vitreous and a half-life of 37 h.
► Effective concentrations in the vitrous 15 days after a bolus injection of 100 ng.
► GDNF was stable in the intraocular environment and induced survival of retinal ganglion cells.
► No complications after injection of pure GDNF into the vitreous.