Single-dose subcutaneous administration of recombinant human parathyroid hormone [rhPTH(1-84)] in healthy postmenopausal volunteers.
BACKGROUND
Parathyroid hormone [PTH(1-84)] is intended for treatment of osteoporosis because it stimulates new bone formation of normal structure and composition. Recently, recombinant human PTH(1-84) [rhPTH(1-84)] has become available for therapeutic evaluation.


OBJECTIVE
To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of rhPTH(1-84) after single-dose subcutaneous administration of rhPTH(1-84) or placebo to 32 healthy postmenopausal volunteers (dose range, 0.02 to 5.0 micrograms.kg-1).


RESULTS
In the lower dose range (0.02 to 2.0 micrograms.kg-1), serum ionized and total calcium concentrations increased dose dependently, with approximately 0.15 mmol/L for dose levels > 0.2 microgram.kg-1 and > 1.5 micrograms.kg-1, respectively, unlike the higher dose range (2.0 to 5.0 micrograms.kg-1), for which concentration-time profiles clearly exhibited a biphasic pattern. Urine evaluation revealed an increase in both calcium/ creatinine and phosphate/creatinine ratios, the former appearing in the 12- to 24-hour and 24- to 36-hour collections for doses > 2.5 micrograms.kg-1 and the latter in the 0- to 12-hour collection for doses > or = 1.5 micrograms.kg-1. Urinary deoxypyridinoline excretion was used as a biochemical marker of bone resorption, but no consistent changes were found. Urinary cyclic adenosine monophosphate excretion, which is an indirect measure of PTH(1-84) action on the kidney, showed a clear increase in the 0- to 12-hour urine collection for doses > or = 1.5 micrograms.kg-1. As for ionized and total calcium, serum concentration-time curves of PTH(1-84) exhibited a double-peak profile, the first peak appearing about 5 to 10 minutes after administration and the second peak occurring about 1 1/2 to 2 hours after administration. Serum terminal half-life of PTH(1-84) was approximately 2 1/2 hours.


CONCLUSIONS
Up to a dose of 5.0 micrograms.kg-1, rhPTH(1-84) was safe and well tolerated by healthy postmenopausal volunteers.
Schwietert
H R
HR
Pharma Bio-Research International BV, Zuidlaren, The Netherlands.
Groen
E W
EW
Sollie
F A
FA
Jonkman
J H
JH
D000328:Adult; D000596:Amino Acids / Q000652:urine; D019540:Area Under Curve; D002118:Calcium / Q000097:blood / Q000378:metabolism* / Q000652:urine; D003404:Creatinine / Q000652:urine; D000242:Cyclic AMP / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D006801:Humans; D007279:Injections, Subcutaneous; D010281:Parathyroid Hormone / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D017698:Postmenopause / Q000097:blood / Q000378:metabolism* / Q000652:urine; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D012016:Reference Values
D000596:Amino Acids; D010281:Parathyroid Hormone; D011994:Recombinant Proteins; C036020:deoxypyridinoline; D003404:Creatinine; D000242:Cyclic AMP; D002118:Calcium