Inter-species differences in sensitivity to the calcemic activity of the novel 1,25-dihydroxyvitamin D3 analog BXL746

The activities of 1,25-dihydroxyvitamin D3 and its synthetic analogs have been extensively studied in humans as well as in preclinical species, and recent data show potential therapeutic utility in cancer treatment. However, their chronic administration leads to changes in blood mineral ion concentrations, and at high doses can result in symptomatic hypercalcemia limiting therapeutic applicability. To overcome this issue, a therapeutic approach based on administration of intermittent, high doses of 1,25(OH)2D3 has been explored in prostate cancer patients. Despite these and other investigations, limited information is available on the effects of acute systemic administration of high doses of 1,25(OH)2D3 or its analogs. Here, we report a comparative analysis of the pro-calcemic effects of the novel 1,25(OH)2D3 analog BXL746 following acute or chronic administration in animals and humans. While chronic administration of BXL746 to rats, dogs and humans leads to similar modulation of calcemia in these species, single dose administration reveals >1000-fold higher sensitivity of dog compared to rat and human in induction of hypercalcemia and consequent systemic toxicity. Our data indicate that the rat is a more relevant species than the dog for the prediction of human results when acute administration of a 1,25(OH)2D3 analog is envisaged.