TY - JOUR
T1 - Pharmacokinetics and pharmacodynamics of subcutaneous recombinant parathyroid hormone (1-84) in patients with hypoparathyroidism
T2 - An open-label, single-dose, phase i study
AU - Clarke, Bart L.
AU - Kay Berg, Jolene
AU - Fox, John
AU - Cyran, Jane A.
AU - Lagast, Hjalmar
N1 - Funding Information:
Dr. Clarke has received institutional research grants from and served as an advisory group member for NPS Pharmaceuticals, Inc. Dr. Berg was an employee of the PRACS Institute, which contracted with NPS Pharmaceuticals, Inc, to perform the study. Drs. Fox and Cyran are consultants for NPS Pharmaceuticals, Inc. Dr. Lagast is an employee of NPS Pharmaceuticals, Inc. This study was funded by NPS Pharmaceuticals, Inc.
Funding Information:
This study was supported by NPS Pharmaceuticals, Inc, which also provided the study drug. The Mayo Clinical Research Unit was supported by grant UL1 TR000135 from the National Center for Advancing Translational Science . Statistical analysis was conducted by Zane Bai and Benjamin Li of NPS Pharmaceuticals. Writing support was provided by Sheila M. Curristin, PhD, of Complete Healthcare Communications, Inc and was funded by NPS Pharmaceuticals.
PY - 2014/5/1
Y1 - 2014/5/1
N2 - 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 t 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.
AB - 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 t 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.
KW - calcium
KW - hypoparathyroidism
KW - parathyroid hormone
KW - pharmacokinetics
KW - phosphate
KW - rhPTH(1-84)
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U2 - 10.1016/j.clinthera.2014.04.001
DO - 10.1016/j.clinthera.2014.04.001
M3 - Article
C2 - 24802860
AN - SCOPUS:84901455066
SN - 0149-2918
VL - 36
SP - 722
EP - 736
JO - Clinical therapeutics
JF - Clinical therapeutics
IS - 5
ER -