Binding to Ocular Albumin as a Half-Life Extension Principle for Intravitreally Injected Drugs: Evidence from Mechanistic Rat and Rabbit Studies.

PURPOSE: The ocular half-life of intravitreally (IVT) injected drugs is of major relevance for the suitability of a drug intended for chronic intraocular treatment, as the half-life determines the dosing frequency. Thus, half-life extension principles are very attractive as they can reduce the IVT dosing frequency. In this study, we investigated the ocular pharmacokinetics (PK) of the IVT injected Nanobody® BI-X and whether the noncovalent binding of BI-X to vitreous albumin could increase its ocular half-life.

METHODS: Wistar rats were dosed IVT with 3 μg BI-X alone or coadministered with human serum albumin (HSA), and the ocular exposure was measured in a pilot experiment using whole eye homogenates. New Zealand White rabbits received IVT injections of 500 μg BI-X alone or coadministration with HSA. Concentrations of BI-X were determined in aqueous humor, vitreous body and plasma and pharmacokinetic parameters were calculated.

RESULTS: Ocular concentrations of BI-X in rats were about 10- or 3-fold higher at 24 and 72 h, respectively, when dosed with HSA. In rabbits, coadministration with albumin led to an about 3-fold increased vitreous half-life and an about 5-fold higher exposure in vitreous humor.

CONCLUSION: As small amounts of albumin are present in the vitreous body of healthy human eyes and the albumin concentration is even increased under disease conditions like diabetic retinopathy, high affinity binding to albumin may be a promising strategy to extend the half-life of IVT injected drugs, allowing for longer dosing intervals.