Chemical formula: C₁₈₁H₂₉₁N₅₅O₅₁S₂ Molecular mass: 4,116.134 g/mol
Endogenous 84-amino-acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidney. Teriparatide (rhPTH(1-34)) is the active fragment (1-34) of endogenous human parathyroid hormone. Physiological actions of PTH include stimulation of bone formation by direct effects on bone forming cells (osteoblasts) indirectly increasing the intestinal absorption of calcium and increasing the tubular re-absorption of calcium and excretion of phosphate by the kidney.
Teriparatide is a bone formation agent to treat osteoporosis. The skeletal effects of teriparatide depend upon the pattern of systemic exposure. Once-daily administration of teriparatide increases apposition of new bone on trabecular and cortical bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity.
The volume of distribution is approximately 1.7 L/kg. The half-life of teriparatide is approximately 1 hour when administered subcutaneously, which reflects the time required for absorption from the injection site.
No metabolism or excretion studies have been performed with teriparatide but the peripheral metabolism of parathyroid hormone is believed to occur predominantly in liver and kidney.
Teriparatide is eliminated through hepatic and extra-hepatic clearance (approximately 62 L/hr in women and 94 L/hr in men).
No differences in teriparatide pharmacokinetics were detected with regard to age (range 31 to 85 years). Dosage adjustment based on age is not required.
Teriparatide was not genotoxic in a standard battery of tests. It produced no teratogenic effects in rats, mice or rabbits. There were no important effects observed in pregnant rats or mice administered teriparatide at daily doses of 30 to 1000 μg/kg. However, fetal resorption and reduced litter size occurred in pregnant rabbits administered daily doses of 3 to 100 μg/kg. The embryotoxicity observed in rabbits may be related to their much greater sensitivity to the effects of PTH on blood ionised calcium compared with rodents.
Rats treated with near-life time daily injections had dose-dependent exaggerated bone formation and increased incidence of osteosarcoma most probably due to an epigenetic mechanism. Teriparatide did not increase the incidence of any other type of neoplasia in rats. Due to the differences in bone physiology in rats and humans, the clinical relevance of these findings is probably minor. No bone tumours were observed in ovariectomised monkeys treated for 18 months or during a 3-year follow-up period after treatment cessation. In addition, no osteosarcomas have been observed in clinical trials or during the post treatment follow-up study.
Animal studies have shown that severely reduced hepatic blood flow decreases exposure of PTH to the principal cleavage system (Kupffer cells) and consequently clearance of PTH (1-84).
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