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. Objectives: 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 mu g . kg(-1)). Results: In the lower dose range (0.02 to 2.0 mu g kg(-1)), serum ionized and total calcium concentrations increased dose dependently, with approximately 0.15 mmol/L for dose levels >0.2 mu g . kg(-1) and >1.5 mu g . kg(-1), respectively, unlike the higher dose range (2.0 to 5.0 mu g . 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 mu g . kg(-1) and the latter in the 0- to 12-hour collection for doses greater than or equal to 1.5 mu g . 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 la-hour urine collection for doses greater than or equal to 1.5 mu g . kg(-1). As for ionized and total calcium, serum concentration-time curves of PTH(1-84) exhibited a double-peak profile, the fist peak appearing about 5 to 10 minutes after administration and the second peak occurring about 11/2 to 2 hours after administration. Serum terminal half-life of PTH(1-84) was approximately 21/2 hours. Conclusion: Up to a dose of 5.0 mu g . kg(-1), rhPTH(1-84) was safe and well tolerated by healthy postmenopausal volunteers.