title: 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.affiliation: Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota. Electronic address: clarke.bart@mayo.edu.
authors.forename: Bart L
authors.initials: BL
authors.lastname: Clarke
authors.affiliation: PRACS Institute, San Antonio, Texas.
authors.forename: Jolene
authors.initials: J
authors.lastname: Kay Berg
authors.affiliation: NPS Pharmaceuticals, Inc, Bedminster, New Jersey.
authors.forename: John
authors.initials: J
authors.lastname: Fox
authors.affiliation: NPS Pharmaceuticals, Inc, Bedminster, New Jersey.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Cyran
authors.affiliation: NPS Pharmaceuticals, Inc, Bedminster, New Jersey.
authors.forename: Hjalmar
authors.initials: H
authors.lastname: Lagast
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002118:Calcium / Q000097:blood; D004334:Drug Administration Schedule; D005260:Female; D020249:Hormone Replacement Therapy / Q000379:methods*; D006801:Humans; D007011:Hypoparathyroidism / Q000188:drug therapy*; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D010281:Parathyroid Hormone / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D014807:Vitamin D / Q000097:blood
chemical_list: D010281:Parathyroid Hormone; D014807:Vitamin D; D002118:Calcium
keywords: calcium; hypoparathyroidism; parathyroid hormone; pharmacokinetics; phosphate; rhPTH(1–84)