Evaluation in vivo of a potent parathyroid hormone antagonist: [Nle^8,18, D-Trp¹², Tyr³⁴]bPTH(7-34)NH₂

In an effort to design and select potent parathyroid hormone (PTH) antagonists suitable for clinical utility, a PTH analog was evaluated in vivo in an animal model to assess its properties in preparation for human studies. The previously described PTH antagonist, [Nle^8,18,D- Trp¹²,Tyr³⁴]bPTH(7-34)NH₂, which is highly active in vitro, was documented in these studies to be an effective antagonist of the PTH- stimulated calcemic response in vivo. In thyroparathyroidectomized (TPTX) rats, the efficacy of the antagonist was demonstrated to be dose-dependent. Inhibition was demonstrated when intravenous administration of antagonist started 1 h prior to coinfusion with the PTH agonist [Nle^8,18,Tyr³⁴]bPTH(1-34)NH₂. Maximal inhibition by antagonist (an 84% decline in serum calcium levels compared with agonist alone) of the calcemic response was observed when a 200-fold molar excess of antagonist (12 nmol/h) was administered. At dose ratios of antagonist:agonist as low as 10:1, a 40- 50% inhibition of PTH-stimulated calcemic response is evident, provided a longer (2 h) lead time for antagonist infusion is allowed. Based on these and related studies, the antagonist [Nle^8,18,D-Trp¹²,Tyr³⁴]bPTH(7- 34)NH₂ has displayed sufficient potency to obtain approval from the appropriate institutional and regulatory agencies for clinical trials in hypercalcemic states of parathyroid and tumor origin.