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

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• 作者：Bart L. Clarke ; MD¹ ; ^{clarke.bart@mayo.edu" class="auth_mail} ; Jolene Kay Berg ; MD² ; ^* ; John Fox ; PhD³ ; Jane A. Cyran ; PhD³ ; Hjalmar Lagast ; MD³
• 关键词：calcium ; hypoparathyroidism ; parathyroid hormone ; pharmacokinetics ; phosphate ; rhPTH(1&ndash ; 84)
• 刊名：Clinical Therapeutics
• 出版年：1 May 2014
• 年：2014
• 卷：36
• 期：5
• 页码：722-736
• 全文大小：439 K

文摘

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_½ 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.