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Boglarka Racz, Konstantin Petrukhin; Unusual pharmacodynamics of the optimized RBP4 antagonist in dogs. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2473.
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© ARVO (1962-2015); The Authors (2016-present)
Accumulation of retinal lipofuscin plays a significant role in pathogenesis of Stargardt disease and, potentially, dry AMD. RBP4 antagonists are known to disrupt the retinol-dependent RBP4-TTR interaction, reduce serum RBP4 and retinol, induce partial depletion of visual cycle retinoids, and inhibit bisretinoid formation in the retina and thus may be considered as a potential therapy for dry AMD and Stargardt disease. We recently identified a novel cyclopentyl fused pyrrolidine RBP4 antagonist BPN-14136 which, in addition to exceptional in vitro potency, was capable of inducing robust RBP4 reduction in rats, mice and non-human primates. Here we present the results of pharmacokinetics (PK) and pharmacodynamics (PD) characterization of BPN-14136 in dogs.
Following the intravenous dose of 0.5 mg/kg or oral dose of 2 mg/kg administration in Beagle dogs, plasma and urine samples were collected at different time points over the period of 48 hours. RBP4 levels were measured using the ELISA kit. A bioanalytical method for analyzing the BPN-14136 concentration involved liquid chromatography with mass spectrometric detection, LC-MS/MS, that was adapted for dog plasma.
While BPN-14136 dosing in mice, rats and non-human primates induced robust reduction in serum RBP4, no such reduction was seen in Beagle dogs despite optimal dog PK characteristics exhibited by BPN-14136. Basal pre-dose levels of serum RBP4 in dogs were drastically lower than in other species studied (rats, mice and non-human primates). These observations are consistent with the previously described unique reliance of carnivorous Canidae species (dog, wolf, coyote, fox) on non-RBP4/TTR dependent mechanisms of retinol delivery to target tissues as the majority of vitamin A is transported in these species by LDL-bound retinyl esters secreted by the liver.
BPN-14136 shows unusual pharmacodynamics in dogs due to the unique reliance of Canidae family on non-RBP4 dependent mechanisms of retinol delivery to target tissues. Because of this species-specific peculiarity in retinol trafficking, dog is not an optimal species for PD characterization of RBP4 antagonists, and canine retinopathy models are not suitable for assessing pre-clinical efficacy of this class of compounds.
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