Pharmacology: Mechanism of Action: Endogenous 84-amino acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidney. Teriparatide 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.
Pharmacodynamic Effects: 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.
Pharmacokinetics: Teriparatide is extensively absorbed after subcutaneous injection; peak plasma concentrations are reached after about 30 minutes. Absolute bioavailability is reported to be about 95%. Teriparatide is eliminated through hepatic and extra hepatic clearance (approximately 62 L/hr in women and 94 L/hr in men). The volume of distribution is approximately 1.7 L/Kg. The half-life of teriparatide is approximately 1 hr. when administered subcutaneously, which reflects the time required for absorption from the injection site. No metabolism or excretion studies with teriparatide have been reported but the peripheral metabolism of parathyroid hormone is believed to occur predominantly in liver and kidney.
Pharmacokinetics in special population: Teriparatide is extensively absorbed after subcutaneous injection; the absolute bioavailability is approximately 95% based on pooled data from 20, 40, and 80-mcg doses. The rates of absorption and elimination are rapid. The peptide reaches peak serum concentrations about 30 minutes after subcutaneous injection of a 20-mcg dose and declines to non-quantifiable concentrations within 3 hours.
Systemic clearance of teriparatide (approximately 62 L/hr in women and 94 L/hr in men) exceeds the rate of normal liver plasma flow, consistent with both hepatic and extra-hepatic clearance. Volume of distribution, following intravenous injection, is approximately 0.12 L/kg. Intersubject variability in systemic clearance and volume of distribution is 25% to 50%. The half-life of teriparatide in serum is 5 minutes when administered by intravenous injection and approximately 1 hour when administered by subcutaneous injection. The longer half-life following subcutaneous administration reflects the time required for absorption from the injection site.
No metabolism or excretion studies have been performed with teriparatide. Peripheral metabolism of PTH is believed to occur by non-specific enzymatic mechanisms in the liver followed by excretion via the kidneys.
Special Populations: Pediatric: Pharmacokinetic data in pediatric patients are not available.
Geriatric: No age-related differences in teriparatide pharmacokinetics were detected (range 31 to 85 years).
Gender: Although systemic exposure to teriparatide was approximately 20% to 30% lower in men than women, the recommended dose for both genders is 20 mcg/day.
Race: The populations included in the pharmacokinetic analyses were 98.5% Caucasian. The influence of race has not been determined.
Renal insufficiency: No pharmacokinetic differences were identified in 11 patients with mild or moderate renal insufficiency [creatinine clearance (CrCl) 30 to 72 mL/min] administered a single dose of teriparatide. In 5 patients with severe renal insufficiency (CrCl <30 mL/min), the AUC and t½ of teriparatide were increased by 73% and 77%, respectively. Maximum serum concentration of teriparatide was not increased. No studies have been performed in patients undergoing dialysis for chronic renal failure.
Heart failure: No clinically relevant pharmacokinetic, blood pressure, or pulse rate differences were identified in 13 patients with stable New York Heart Association Class I to III heart failure after the administration of two 20-mcg doses of teriparatide.
Hepatic insufficiency: Non-specific proteolytic enzymes in the liver (possibly Kupffer cells) cleave PTH(1-34) and PTH(1-84) into fragments that are cleared from the circulation mainly by the kidney. No studies have been performed in patients with hepatic impairment.
Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Two carcinogenicity bioassays were conducted in Fischer 344 rats. In the first study, male and female rats were given daily subcutaneous teriparatide injections of 5, 30, or 75 mcg/kg/day for 24 months from 2 months of age. These doses resulted in systemic exposures that were, respectively, 3, 20, and 60 times higher than the systemic exposure observed in humans following a subcutaneous dose of 20 mcg (based on AUC comparison). Teriparatide treatment resulted in a marked dose-related increase in the incidence of osteosarcoma, a rare malignant bone tumor, in both male and female rats. Osteosarcomas were observed at all doses and the incidence reached 40% to 50% in the high-dose groups. Teriparatide also caused a dose-related increase in osteoblastoma and osteoma in both sexes. No osteosarcomas, osteoblastomas or osteomas were observed in untreated control rats. The bone tumors in rats occurred in association with a large increase in bone mass and focal osteoblast hyperplasia.
The second 2-year study was carried out in order to determine the effect of treatment duration and animal age on the development of bone tumors. Female rats were treated for different periods between 2 and 26 months of age with subcutaneous doses of 5 and 30 mcg/kg (equivalent to 3 and 20 times the human exposure at the 20-mcg dose, based on AUC comparison). The study showed that the occurrence of osteosarcoma, osteoblastoma and osteoma was dependent upon dose and duration of exposure. Bone tumors were observed when immature 2-month old rats were treated with 30 mcg/kg/day for 24 months or with 5 or 30 mcg/kg/day for 6 months. Bone tumors were also observed when mature 6-month old rats were treated with 30 mcg/kg/day for 6 or 20 months. Tumors were not detected when mature 6-month old rats were treated with 5 mcg/kg/day for 6 or 20 months. The results did not demonstrate a difference in susceptibility to bone tumor formation, associated with teriparatide treatment, between mature and immature rats.
The relevance of these rat findings to humans is uncertain.
Mutagenesis: Teriparatide was not genotoxic in any of the following test systems: the Ames test for bacterial mutagenesis; the mouse lymphoma assay for mammalian cell mutation; the chromosomal aberration assay in Chinese hamster ovary cells, with and without metabolic activation; and the in vivo micronucleus test in mice.
Impairment of fertility: No effects on fertility were observed in male and female rats given subcutaneous teriparatide doses of 30, 100, or 300 mcg/kg/day prior to mating and in females continuing through gestation Day 6 (16 to 160 times the human dose of 20 mcg based on surface area, mcg/m2).
Pregnancy: Pregnancy Category C: In pregnant rats given subcutaneous teriparatide doses up to 1000 mcg/kg/day, there were no mortality. In pregnant mice given subcutaneous doses of 225 or 1000 mcg/kg/day (≥ 60 times the human dose based on surface area, mcg/m2) from gestation Day 6 through 15, the fetuses showed an increased incidence of skeletal deviations or variations (interrupted rib, extra vertebra or rib).
Developmental effects in a perinatal/postnatal study in pregnant rats given subcutaneous doses of teriparatide from gestation day 6 through postpartum Day 20 included mild growth retardation in female offspring at doses ≥ 225 mcg/kg/day (≥ 120 times the human dose based on surface area, mcg/m2), and in male offspring at 1000 mcg/kg/day (540 times the human dose based on surface area, mcg/m2). There was also reduced motor activity in both male and female offspring at 1000 mcg/kg/day. There were no developmental or reproductive effects in mice or rats at a dose of 30 mcg/kg (8 or 16 times the human dose based on surface area, mcg/m2). The effect of teriparatide treatment on human fetal development has not been studied. Teriparatide (rDNA origin) is not indicated for use in pregnancy.
Nursing Mothers: Because Teriparatide (rDNA origin) is indicated for the treatment of osteoporosis in postmenopausal women, it should not be administered to women who are nursing their children. There have been no clinical studies to determine if teriparatide is secreted into breast milk.
Pediatric Use: The safety and efficacy of Teriparatide (rDNA origin) have not been established in pediatric populations. Teriparatide is not indicated for use in pediatric patients.
Geriatric Use: Of the patients receiving Teriparatide (rDNA origin) in the osteoporosis trial of 1637 postmenopausal women, 75% were 65 years of age and over and 23% were 75 years of age and over. Of the patients receiving Teriparatide in the osteoporosis trial of 437 men, 39% were 65 years of age and over and 13% were 75 years of age and over. No significant differences in bone response or adverse reactions were seen in geriatric patients receiving Teriparatide as compared with younger patients. Nonetheless, as with many medications, elderly patients may have greater sensitivity to the adverse effects of Teriparatide.