, Volume 65, Issue 4, pp 559-576
Date: 17 Sep 2012

Paricalcitol

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Summary

Abstract

Paricalcitol (Zemplar®) is a synthetic vitamin D2 analogue that inhibits the secretion of parathyroid hormone (PTH) through binding to the vitamin D receptor. It is approved in the US and in most European nations for intravenous use in the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure in adult, and in the US paediatric, patients.

Paricalcitol effectively reduced elevated serum PTH levels and was generally well tolerated in children and adults with secondary hyperparathyroidism associated with chronic renal failure. In well designed clinical trials, paricalcitol was as effective as calcitriol and as well tolerated in terms of the incidence of prolonged hypercalcaemia and/or elevated calcium-phosphorus product (Ca × P). Thus, paricalcitol is a useful option for the management of secondary hyperparathyroidism in adults and children with chronic renal failure.

Pharmacological Properties

Paricalcitol (19-nor-1,25-dihyroxyvitamin D2) mimics the actions of 1,25-dihydroxyvitamin D3 (calcitriol), at the vitamin D receptor. This receptor heterodimerises the retinoid X receptor to regulate transcriptional activity of vitamin D-responsive genes.

In rats, paricalcitol inhibits the secretion of PTH in a dose-dependent manner, and suppresses parathyroid hyperplasia. Paricalcitol stimulates less osteoclastic activity than calcitriol and induces similar inhibition of osteoblast maturation in vitro. In rodent models, paricalcitol stimulates less intestinal calcium uptake and is 10-fold less active in the mobilisation of skeletal calcium and phosphorus in vivo than calcitriol.

Intravenous paricalcitol absorption is dose proportional, with little evidence of accumulation of the drug after repeated doses in healthy volunteers or in haemodialysis patients. Mean maximum plasma concentration and area under the plasma concentration-time curve from 0 to 44 hours were 4566 pg/mL and 18 232 pg · h/mL after 4 weeks’ treatment with paricalcitol 0.16 μg/kg three times weekly in haemodialysis patients. The drug is extensively bound to plasma proteins (>99.9%).

Paricalcitol elimination, primarily by biliary excretion, is biphasic. Paricalcitol was metabolised by the cytochrome P450 enzyme 24-hydroxylase in vitro, and only 5.7% of an intravenous dose of the drug was excreted unchanged in healthy volunteers. In patients undergoing haemodialysis, paricalcitol clearance was 0.58–0.91 L/h, and the terminal elimination half-life was 11–32 hours; clearance did not appear to be altered by haemodialysis, indicating that paricalcitol may be administered at any time during haemodialysis.

Therapeutic Efficacy

Intravenous paricalcitol is effective in the treatment of secondary hyperparathyroidism associated with chronic renal failure. In patients undergoing maintenance haemodialysis, paricalcitol reduced mean serum intact PTH (iPTH) levels from ≥650 pg/mL to <300 pg/mL in 18–19 weeks and these reductions were proportionally similar to those evoked by calcitriol therapy.

In calcitriol-resistant patients on maintenance haemodialysis, a switch to paricalcitol therapy elicited a sustained reduction in serum iPTH levels, while in children and young adults, paricalcitol reduced serum iPTH levels without increasing the incidence of elevated serum calcium or phosphorus levels.

Both paricalcitol and calcitriol evoked reductions in serum alkaline phosphatase levels, indicating reductions in bone turnover.

Tolerability

Morbidity and mortality data from analysis of a historical cohort indicate that, over a 36-month period in patients undergoing haemodialysis, paricalcitol provided a 16% survival advantage over calcitriol. Therapy with paricalcitol had little effect on serum calcium and phosphorus levels, and differences in the effect of paricalcitol compared with calcitriol on the induction of single episodes or prolonged periods of hypercalcaemia and/or elevated Ca × P were equivocal.

In calcitriol-resistant patients switched to paricalcitol therapy, use of a calcitriol: paricalcitol dose conversion ratio of 1: 3 minimised increases in serum calcium levels. In children and young adults receiving maintenance haemodialysis, paricalcitol use did not cause increases in serum calcium or phosphorus levels.

Other adverse events reported by patients treated with paricalcitol included nausea, vomiting and oedema.