Pharmacokinetics and pharmacodynamics of subcutaneous recombinant parathyroid hormone (1-84) in patients with hypoparathyroidism: an open-label, single-dose, phase I study.

Abstract

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 µg and then 100 µg 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 µg/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-µg rhPTH(1-84) dose, had at least a 7-day washout interval, and then received a single 100-µg 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 µg (n = 6) and 100 µg (n = 7), the approximate t½ was 2.5 to 3 hours. Plasma PTH levels increased rapidly, then declined gradually back to predose levels at ~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 µg reduced 24-hour calcium excretion and calcium-to-creatinine ratios by 12% and 23%, respectively, and rhPTH(1-84) 100 µg reduced them by 26% and 27%. There was little overall impact on urine magnesium levels. Compared with calcitriol, rhPTH(1-84) 50 µg increased urinary phosphate excretion and phosphate-to-creatinine ratios by 53% and 54%, respectively, and rhPTH(1-84) 100 µg increased them by 45% and 42%. Urine cyclic adenosine monophosphate-to-creatinine ratio increased with rhPTH(1-84) by 2.3-fold (50 µg) and 4.4-fold (100 µg) 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 hypoparathyroidism.

• Authors: Bart L Clarke, Jolene Kay Berg, John Fox, Jane A Cyran, Hjalmar Lagast
• Journal: Clinical therapeutics (Clin Ther) Vol. 36 Issue 5 Pg. 722-36 (May 2014) ISSN: 1879-114X [Electronic] United States
• PMID: 24802860 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Authors. Published by EM Inc USA.. All rights reserved.

Chemical References

• Parathyroid Hormone
• Vitamin D
• Calcium

Topics

• Adult
• Aged
• Aged, 80 and over
• Calcium (blood)
• Drug Administration Schedule
• Female
• Hormone Replacement Therapy (methods)
• Humans
• Hypoparathyroidism (drug therapy)
• Injections, Subcutaneous
• Male
• Middle Aged
• Parathyroid Hormone (administration & dosage, blood, pharmacokinetics)
• Vitamin D (blood)