Pharmacokinetics and Pharmacodynamics of Subcutaneous Recombinant Parathyroid Hormone (1-84) in Patients With Hypoparathyroidism: An Open-Label, Single-Dose, Phase I Study

Background: Impaired mineral homeostasis affecting calcium, phosphate, and magnesium is a result of parathyroid hormone (PTH) deficiency in hypoparathyroidism. The current standard of treatment with active vitamin D and oral calcium does not control levels of these major minerals. Recombinant full-length human PTH 1-84 (rhPTH[1-84]) is being developed for the treatment of hypoparathyroidism. Objective: The goal of this study was to investigate the pharmacokinetics and pharmacodynamics of a single subcutaneous injection of rhPTH(1-84) in patients with hypoparathyroidism. Methods: This was an open-label, dose-escalating study of single subcutaneous administration of 50 mu g and then 100 mu g of rhPTH(1-84). Enrolled patients (age range, 25-85 years) had >= 12 months of diagnosed hypoparathyroidism defined according to biochemical evidence of hypocalcemia with concomitant low-serum intact PTH and were taking doses >= 1000 mg/d of oral calcium and >= 0.25 mu g/d of active vitamin D (oral calcitriol). The patient's prescribed dose of calcitriol was taken the day preceding but not on the day of or during the 24 hours after rhPTH(1-84) administration. Each patient received a single 50-mu g rhPTH(1-84) dose, had at least a 7-day washout interval, and then received a single 100-mu g rhPTH(1-84) dose. The following parameters were assessed: plasma PTH; serum and urine total calcium, magnesium, phosphate, and creatinine; and urine cyclic adenosine monophosphate. Results: After administration of rhPTH(1-84) 50 mu g (n = 6) and 100 mu g (n = 7), the approximate t(1/2) was 2.5 to 3 hours. Plasma PTH levels increased rapidly, then declined gradually back to predose levels at similar to 12 hours. The median AUC was similar with calcitriol and rhPTH(1-84) for serum 1,25-dihydroxyvitamin D (calcitriol, 123-227 pg . h/mL; rhPTH[1-84], 101-276 pg . h/mL), calcium (calcitriol, 3.3-3.7 mg . h/dL; rhPTH[1-84], 3.3-7.6 mg . h/dL), and magnesium (calcitriol, 0.7-0.9 mg . h/dL; rhPTH[1-84], 1.3-2.8 mg . h/dL). In contrast, the median AUC for phosphate was strongly negative with rhPTH(1-84) (calcitriol, -1.0 to 0.8 mg . h/dL; rhPTH[1-84], -21.3 to -26.5 mg . h/dL). Compared with calcitriol, rhPTH(1-84) 50 mu g reduced 24-hour calcium excretion and calcium-to-creatinine ratios by 12% and 23%, respectively, and rhPTH(1-84) 100 mu g reduced them by 26% and 27%. There was little overall impact on urine magnesium levels. Compared with calcitriol, rhPTH(1-84) 50 mu g increased urinary phosphate excretion and phosphate-to-creatinine ratios by 53% and 54%, respectively, and rhPTH(1-84) 100 mu g increased them by 45% and 42%. Urine cyclic adenosine monophosphate to creatinine ratio increased with rhPTH(1-84) by 2.3-fold (50 mu g) and 4.4-fold (100 mu g) compared with calcitriol. Conclusions: PTH replacement therapy with rhPTH(1-84) regulated mineral homeostasis of calcium, magnesium, phosphate, and vitamin D metabolism toward normal in these study patients with hyp op arathyroidism. (C) 2014 The Authors. Published by Elsevier HS Journals, Inc. All rights reserved.