Endogenous parathyroid hormone (PTH) is secreted by the parathyroid glands as a polypeptide of 84 amino acids. PTH exerts its action via cell-surface parathyroid hormone receptors, present in bone, kidney and nerve tissue. Parathyroid hormone receptors belong to the family of G-coupled protein receptors.
PTH has a variety of critical physiological functions that include its central role in modulating serum calcium and phosphate levels within tightly regulated levels, regulating renal calcium and phosphate excretion, activating vitamin D, and maintaining normal bone turnover.
PTH (1-84) is the principal regulator of plasma calcium homeostasis. In the kidney, PTH (1-84) increases renal tubular reabsorption of calcium and promotes phosphate excretion.
The overall effect of PTH is to increase serum calcium concentration, to reduce urinary excretion of calcium and to lower serum phosphate concentration.
The pharmacokinetics of parathyroid hormone following subcutaneous administration in the thigh of hypoparathyroidism subjects was consistent with that observed in healthy post-menopausal women who received parathyroid hormone in the thigh and abdomen.
Parathyroid hormone administered subcutaneously had an absolute bioavailability of 53%.
Following intravenous administration, parathyroid hormone has a volume of distribution of 5.35 L at steady state.
In vitro and in vivo studies demonstrated that the clearance of parathyroid hormone is primarily a hepatic process with a lesser role played by the kidneys.
In the liver, parathyroid hormone is cleaved by cathepsins. In the kidney, parathyroid hormone and C-terminal fragments are cleared by glomerular filtration.
Parathyroid hormone (rDNA) was evaluated in an open-label PK/PD study in which 7 patients with hypoparathyroidism received single subcutaneous doses of 50 and 100 micrograms with a 7-day washout interval between doses.
Peak plasma concentrations (mean Tmax) of parathyroid hormone occur within 5 to 30 minutes and a second usually smaller peak at 1 to 2 hours. The apparent terminal half-life (t1/2) was 3.02 and 2.83 hours for the 50 and 100 micrograms dose, respectively. The maximum mean increases of serum calcium, which occurred at 12 hours, were approximately 0.125 mmol/L and 0.175 mmol/L with the 50 micrograms and 100 micrograms dose, respectively.
Treatment with parathyroid hormone increases serum calcium concentration in hypoparathyroidism patients, and this increase occurs in a dose-related manner. After a single injection of parathyroid hormone (rDNA), the mean serum total calcium reached its peak level between 10 and 12 hours. The calcaemic response is sustained for more than 24 hours after administration.
Treatment with parathyroid hormone produces a decrease in urinary calcium excretion by 13 and 23% (50 and 100 microgram dose, respectively) to a nadir in the 3 to 6 hour time point, which returns to pre-dosing levels by 16 to 24 hours.
Following injection with parathyroid hormone, serum phosphate levels decrease proportionally to PTH levels over the first 4 hours and persist over 24 hours post-injection.
Serum 1,25-(OH)2D increases following a single dose of parathyroid hormone to maximum levels at about 12 hours with a return to near baseline levels by 24 hours. A greater increase in the levels of 1,25-(OH)2D in serum were observed with the 50 micrograms dose than with the 100 micrograms dose, likely due to direct inhibition of the renal 25-hydroxyvitamin D-1-hydroxylase enzyme by serum calcium.
A pharmacokinetic study in non-hypoparathyroidism subjects was conducted in 6 men and 6 women with moderate hepatic impairment (Child-Pugh Classification of 7-9 [Grade B]) as compared with a matched group of 12 subjects with normal hepatic function. Following a single 100 micrograms subcutaneous dose, the mean Cmax and baseline-corrected Cmax values were 18% to 20% greater in the moderately impaired subjects than in those with normal function. There were no apparent differences in the serum total calcium concentration-time profiles between the 2 hepatic function groups. No dose adjustment for parathyroid hormone is recommended in patients with mild to moderate hepatic impairment. There are no data in patients with severe hepatic impairment.
Pharmacokinetics following a single 100 micrograms subcutaneous dose of parathyroid hormone was evaluated in 16 non-impaired subjects (creatinine clearance (CLcr) >80 mL/min) and 16 subjects with renal impairment. The mean maximum concentration (Cmax) of PTH following 100 micrograms parathyroid hormone (rDNA) in subjects with mild-to-moderate renal impairment (CLcr 30 to 80 mL/min) was approximately 23% higher than that observed in subjects with normal renal function. Exposure to PTH as measured by AUC0-last and baseline-corrected AUC0-last was approximately 3.9% and 2.5%, respectively, higher than that observed for subjects with normal renal function.
Based on these results, no dose adjustment is necessary in patients with mild-to-moderate renal impairment (CLcr 30 to 80 mL/min). No studies were conducted in patients on renal dialysis. There are no data in patients with severe renal impairment.
Pharmacokinetic data in paediatric patients are not available.
Clinical studies with parathyroid hormone did not include sufficient numbers of subjects aged 65 and over to determine whether response in these subjects is different from younger subjects.
No clinically relevant gender differences were observed in the REPLACE study.
No dose adjustment is necessary based on weight.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, mutagenicity, toxicity to fertility and general reproduction, and local tolerance.
Rats treated with daily injections of parathyroid hormone for 2 years had dose-dependent exaggerated bone formation and an increased incidence of bone tumours, including osteosarcoma, most probably due to a non-genotoxic mechanism. Due to the differences in bone physiology in rats and humans, the clinical relevance of these findings is unknown. No osteosarcomas have been observed in clinical trials.
Parathyroid hormone did not adversely affect fertility or early embryonic development in rats, embryo-foetal development in rats and rabbits, or pre/post-natal development in rats. A minimal amount of parathyroid hormone is excreted in the milk of lactating rats.
In monkeys receiving daily subcutaneous doses for 6 months, there was an increased occurrence of renal tubular mineralisation at exposure levels 2.7 times the clinical exposure levels at the highest dose.
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