Paricalcitol

ADIS DRUG EVALUATION

Drugs 2005; 65 (4): 559-576 0012-6667/05/0004-0559/$39.95/0 © 2005 Adis Data Information BV. All rights reserved.

Paricalcitol A Review of its Use in the Management of Secondary Hyperparathyroidism Dean M. Robinson and Lesley J. Scott Adis International Limited, Auckland, New Zealand Various sections of the manuscript reviewed by: A.J. Brown, Renal Division, Washington University School of Medicine, St Louis, Missouri, USA; J. Cunningham, University College London, The Middlesex Hospital, London, UK; A.S. Dusso, Renal Division, Washington University School of Medicine, St Louis, Missouri, USA; K.J. Martin, Division of Nephrology, Saint Louis University School of Medicine, St Louis, Missouri, USA; C.W. McIntyre, Department of Renal Medicine, Derby City General Hospital, Derby, UK; K.C. Norris, School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA; C.P. Sanchez, Department of Pediatrics, University of Wisconsin Medical School, Madison, Wisconsin, USA. Data Selection Sources: Medical literature published in any language since 1980 on paricalcitol, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug. Search strategy: Medline search terms were ‘paricalcitol’. EMBASE search terms were ‘paricalcitol’. AdisBase search terms were ‘paricalcitol’. Searches were last updated 18 January 2005. Selection: Studies in patients with secondary hyperparathyroidism who received paricalcitol. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included. Index terms: Paricalcitol, secondary hyperparathyroidism, renal failure, paediatric, pharmacodynamics, pharmacokinetics, therapeutic use.

Contents Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 560 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561 2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562 2.1 Effects on Parathyroid Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562 2.2 Effects on Bone Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563 2.3 Effects on Calcium and Phosphorus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563 2.4 Other Actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564 3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564 3.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564 3.2 Metabolism and Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565 4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565 4.1 In Adult Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566 4.1.1 Versus Placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566 4.1.2 Versus Calcitriol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566 4.1.3 Longer-Term Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569 4.2 In Children and Young Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570 5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570 6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571 7. Place of Paricalcitol in the Management of Secondary Hyperparathyroidism . . . . . . . . . . . . . . . . . . 572

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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 Dresponsive 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 6.5 mg/dL have a 41% (p < 0.0005) higher risk of death resulting from coronary artery disease.[13] A recent, large analysis has indicated that serum phosphorus levels of >5.0 mg/dL and serum calcium levels, adjusted for serum albumin, of >8.0 mg/dL are associated with an increased relative risk of death.[14] In children and young adults, significant features of secondary hyperparathyroidism include bone deformity and growth impairment (reviewed by Sanchez[15]), which may result not only from changes in serum levels of PTH, calcitriol, calcium and phosphorus, but also from metabolic acidosis.[16] Treatment of secondary hyperparathyroidism with injectable vitamin D is associated with a significant reduction in mortality rate.[17] However, while intravenous administration of calcitriol suppresses PTH secretion, the increase in calcitriol often leads to the development of hypercalcaemia and greater hyperphosphataemia (figure 1), which may be further aggravated by the use of calcium-containing phosphate binders in dialysis patients.[18] Paricalcitol (19-nor-1,25-dihydroxyvitamin D2, Zemplar®)1 is a synthetic vitamin D2 analogue with

The use of trade names is for identification purposes only and does not imply endorsement.

© 2005 Adis Data Information BV. All rights reserved.

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Stimulatory Inhibitory

Parathyroid gland

PTH

25-hydroxyvitamin D3

1α-hydroxylase Bone turnover 1,25-dihydroxyvitamin D3 (calcitriol)

Intestinal absorption

↑Calcium ↑Phosphorus

Kidney reabsorption CYP24

1,24,25-trihydroxyvitamin D3 Fig. 1. Interrelationship between calcium, phosphorus, calcitriol and parathyroid hormone (PTH) during normal parathyroid function. Synthesis and degradation of calcitriol (1,25-dihydroxyvitamin D3) by 1α-hydroxylase and 24-hydroxylase (cytochrome P450 [CYP] 24); the metabolic actions of calcitriol; and the stimulation or inhibition of 1α-hydroxylase, CYP24, bone metabolism and renal or intestinal calcium absorption by serum levels of calcium, phosphorus, calcitriol and PTH.[4,7,8]

the characteristic vitamin D2 methyl group and a carbon double bond on its side chain, but lacking the normal exocyclic C-19 methylene group (figure 2). Paricalcitol has been approved by the US FDA for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure in adult and paediatric patients.[19] This article reviews the use of intravenous paricalcitol in the treatment of secondary hyperparathyroidism.

where it heterodimerises the retinoid X receptor (RXR) and regulates transcriptional activity in the nucleus.[20] The VDR-RXR heterodimer binds to specific DNA elements in the promoter region of vitamin D-responsive genes and also interacts with various nuclear proteins that form a functional transcriptional initiation complex to determine the rate of vitamin D-dependent gene transcription (reviewed by Dusso et al.[20]). Paricalcitol mimics the action of calcitriol at the VDR. The affinity of paricalcitol for the VDR is less than that of calcitriol, with a 7-fold lower relative affinity.[21] It has been suggested that the binding of various vitamin D analogues to the VDR may differ from that of calcitriol and result in conformational changes that lead to variable VDR-mediated transcription,[20] although crystal-structure analysis indicates no difference in conformation of the ligand binding domain with different ligands.[22] Modulation of calcitriol/VDR function in a cell and ligand specific fashion may also derive from several intracellular proteins (e.g. intracellular vitamin D binding proteins[23] and Ski-interacting protein[24]) that are involved in the association and dissociation of calcitriol to the VDR. 2.1 Effects on Parathyroid Glands

Paricalcitol selectively inhibited PTH secretion as effectively as calcitriol, probably through a common transcriptional repression mechanism,[25] both in vitro, in a dose-dependent manner,[25] and in vivo.[26-28] The paricalcitol dose required to inhibit PTH secretion was 3- to 10-fold higher than the calcitriol dose needed to achieve this effect.[26-28] In addition to suppression of PTH synthesis, paricalcitol also inhibits parathyroid gland hyperplasia.[27,28] In uraemic rats, parathyroid gland weight

2. Pharmacodynamic Properties Data on the effects of paricalcitol on serum PTH, calcium and phosphorus levels in patients with secondary hyperparathyroidism are discussed in section 4. Most of the data reviewed in this section are from in vitro and in vivo animal studies (table I). The actions of vitamin D are mediated by the vitamin D receptor (VDR) which, when ligand bound, translocates from the cytosol to the nucleus, © 2005 Adis Data Information BV. All rights reserved.

H

CH3

H

CH3 CH3

CH3 H

OH CH3

OH

H

OH H Fig. 2. Structure of paricalcitol.

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Paricalcitol in Secondary Hyperparathyroidism

Table I. Overview of the pharmacodynamic properties of paricalcitol from in vitro and in vivo animal studies Effects on parathyroid glands Selectively inhibits PTH secretion in vitro[25] and in vivo[26-28] Suppresses parathyroid gland hyperplasia[27] Reduces serum PTH levels in short[25] and medium term[26,27] Effects on calcium and phosphorus Minimal effect on serum calcium and/or phosphorus levels[25,27] Small increase in intestinal calcium and phosphorus absorption in normal rats[29,30] Less potent than calcitriol in the time-dependent stimulation of intestinal calcium absorption in vitamin D-deficient rats[31] High dosages reduce intestinal vitamin D receptor content[27] Less potent than calcitriol in stimulating expression of intestinal calcium-handling proteins[30] Increases urinary excretion of calcium but not phosphorus[29] Effects on bone metabolism Less potent than calcitriol in mobilising calcium and phosphorus from bone in vitrol[32,33] and in vivo[26,31,34] Corrects abnormal bone metabolism in rats with established secondary hyperparathyroidism[26] Less potent than calcitriol in stimulating osteoclastic activity[32,33] and similar inhibition of osteoblastic maturation[32] Other tissues Increases susceptibility of proximal tubular cells to oxidative damage[35] PTH = parathyroid hormone.

increased by 40–50% following nephrectomy, but this increase was prevented[28] or inhibited[27] by treatment with paricalcitol. Serum levels of PTH are reduced in both the short (8 days)[25] and medium (8 weeks)[26,27] term in animal models of uraemia. 2.2 Effects on Bone Metabolism

Vitamin D plays an important role in bone metabolism independent of its effects on serum PTH, as exemplified by recent work with double knockout mice lacking VDR and 1α-hydroxylase.[36] Paricalcitol appears to be less potent in vitro than calcitriol in the stimulation of bone resorption.[37] To cause a significant increase (p < 0.05) in acid phosphatase release, higher concentrations of paricalcitol than calcitriol were required (10–8 vs 10–9 mol/L), suggesting less potent promotion of osteoclastic activity.[32] In mouse bone marrow cultures, while 5 days exposure to 10 nmol/L calcitriol or paricalcitol stimulated dentine resorption by osteoclasts, the area resorbed by paricalcitol-stimulated osteoclasts © 2005 Adis Data Information BV. All rights reserved.

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was 63% less than that resorbed by calcitriol-stimulated osteoclasts (p < 0.05).[33] This difference could only partly be explained by a 20% higher rate of paricalcitol degradation. Calcitriol and paricalcitol appear to have similar potential to stimulate bone formation. In MG-63 osteoblast-like cells, paricalcitol and calcitriol had similar potency in upregulating VDR content, suppressing proliferation (indicated by increased alkaline phosphatase activity) and inducing the release of osteocalcin, a marker of mature osteoblast activity.[38] In mouse calvariae, calcitriol, but not paricalcitol, suppressed alkaline phosphatase release,[32] while the release of osteocalcin was induced at a concentration of calcitriol an order of magnitude lower than that of paricalcitol in one study[32] but at the same concentration in another.[37] A difference in the rate of bone demineralisation stimulated by calcitriol and paricalcitol emerges over time.[31,32,34] In cultured neonatal mouse calvariae in vitro, exposure to either calcitriol or paricalcitol for 48 hours increased calcium efflux from bone 1.5- to 2.6-fold (p < 0.05 vs baseline), with the increase in efflux occurring at a lower concentration of paricalcitol than calcitriol.[32] However, in vivo in vitamin D-deficient rats, a 7-day course of calcitriol 240 pmol induced greater calcium mobilisation than daily paricalcitol 240 pmol, although in the first 24–72 hours bone calcium mobilisation was similar.[31] In parathyroidectomised rats fed calcium- or phosphorus-deficient diets, paricalcitol treatment for 9 days was 10-fold less effective at mobilising calcium and phosphorus from the skeleton compared with calcitriol.[34] In rats, paricalcitol prevented the histomorphometric changes produced by uraemia-induced secondary hyperparathyroidism when therapy began immediately after nephrectomy, but a clinically more relevant observation was that it also corrected abnormal bone metabolism in rats with established secondary hyperparathyroidism.[26] 2.3 Effects on Calcium and Phosphorus

Paricalcitol had a minimal effect on serum calcium and/or phosphorus levels in animal models, and was 10-fold less active than calcitriol.[25,27] In addition, paricalcitol resulted in increases from baseline Drugs 2005; 65 (4)

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in the fraction of ingested calcium (by 3–11%) and phosphorus (by 2–9%) absorbed in normal rats that were significant (p < 0.05 and p < 0.01) in one study[30] but not the other.[29] Significant (p < 0.05 and p < 0.01) increases in calcium and phosphorus absorption were induced by 5- to 10-fold lower concentrations of calcitriol.[29,30] A time-dependent difference in intestinal calcium absorption stimulated by calcitriol and paricalcitol has been observed in vitamin D-deficient rats.[31] A 7-day course of intravenous paricalcitol 600 pmol or calcitriol 600 pmol every other day elicited significantly larger increases (p < 0.05) in intestinal calcium transport in the calcitriol-treated rats although intestinal calcium transport after 24 hours did not differ. These differences in the intestinal uptake of calcium between calcitriol and paricalcitol do not seem to be due, at least in the short term, to differences in VDR levels, which were similar in normal rats receiving intraperitoneal injections of either calcitriol 240 pmol or paricalcitol 240 pmol every other day for a week (183 vs 208 fmol/mg protein).[31] Instead, they may may derive from differences in the expression of calcium-handling proteins.[30] However, in longer trials, after 8 weeks of treatment with higher dosages of paricalcitol (75 or 300 ng/week), significant (p < 0.05) reductions in intestinal VDR content compared with calcitriol treatment (18 ng/week) were observed, perhaps as a result of a decline in endogenous calcitriol which was correlated with VDR content (r = 0.963; p = 0.0083).[27] Calcitriol, but not paricalcitol, significantly (p < 0.01) increased urinary phosphorus excretion in rats, whereas both treatments significantly (p < 0.05) increased calcium excretion.[29] 2.4 Other Actions

Both in vitro and in vivo experiments indicate that, although they had no direct effect on human proximal tubular cell viability, calcitriol increased susceptibility to ATP-depletion/Ca2+-ionophoremediated and oxidative Fe-mediated attack, whereas paricalcitol increased susceptibility only to prolonged oxidative Fe-mediated attack.[35] Calcitriol has a diverse range of biological activities in many parts of the body. Calcitriol is involved © 2005 Adis Data Information BV. All rights reserved.

in a variety of hyperproliferative disorders, including cancer, psoriasis and immune dysfunction, and also elicits rapid non-genomic responses in a number of tissues, through an unknown receptor that may be functionally linked to the VDR.[5] Whether paricalcitol has similar activity has not been examined, although a pilot study has investigated its use in psoriasis,[39] but given its mode of action and similarity to calcitriol it seems likely that it will play a similar role. 3. Pharmacokinetic Properties The single-dose pharmacokinetics of intravenous paricalcitol were examined in two nonblind trials in four healthy volunteers receiving a single bolus dose of tritiated paricalcitol 0.16 μg/kg[40,41] and in six patients receiving a single dose of paricalcitol 0.08 μg/kg ≈2 hours prior to haemodialysis.[42] Two randomised, double-blind trials investigated the pharmacokinetics of paricalcitol following repeated administration in 18 healthy volunteers[41,43] and in 16 haemodialysis patients[41,44] (see table II for further study details). Three of the studies[40,43,44] are available only as abstracts and additional details were obtained from an FDA medical review.[41] 3.1 Absorption and Distribution

In healthy volunteers, the mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were dose proportional after one and three doses (table II).[43] While the AUC after 44 hours (AUC44) observed in haemodialysis patients after a 4-week period of treatment[44] was substantially higher than the AUC extrapolated to infinity (AUC∞) in healthy volunteers[43] (table II), little or no drug accumulation was reported between the first and twelfth doses.[44] Indeed, mean Cmax and AUC44 values for patients receiving the highest dose were lower after the last dose than after the first (1728 vs 1951 pg/mL) and 25 662 vs 28 671 pg • h/mL).[41] Paricalcitol distribution into erythrocytes was negligible, while plasma protein binding was >99.9% and independent of concentration over the range 1–100 ng/mL.[40,41] Drugs 2005; 65 (4)

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Table II. Mean pharmacokinetic parameters of intravenous paricalcitol (PAR) in healthy volunteers[41,43] and in patients undergoing haemodialysis[41,44] participating in randomised, double-blind trials Study

na

PAR regimen (μg/kg)

4 (2)

0.04 SD

256

683

4.2

2.7*

17

0.04 3D

232

1077

2.5

5.6

25

0.08 SD

664

2221

2.7

5.3*

20

0.08 3D

553

2104

3.0

4.8

20

0.16 SD

1242

5247

2.4

7.3*

23

0.16 3D

1061

5331

2.4

6.8

22

34

Cmax (pg/mL)

AUCb (pg • h/mL)

CL (L/h)

t1/2γc (h)

Vss (L)

Healthy volunteers Slatopolsky et al.[43]d,e

4 (4) 4 (4)

Haemodialysis patients Cato et al.[44]d,f

a

6 (3)

0.04 tiw × 4wk

253

6094

0.69

32.0

3 (2)

0.08 tiw × 4wk

1656

14 399

0.58

11.3

9

1 (1)

0.16 tiw × 4wk

4566

18 232

0.91

25.0

31

6 (5)

0.24 tiw × 4wk

1850

27 382

0.72

13.6

6

Number of volunteers[43] or haemodialysis patients[44] for Cmax (n for other parameters).

b

AUC calculated from 0 to 44h[41,44] or extrapolated to infinity.[41,43]

c

Harmonic mean.

d

Studies available as abstracts. Data also obtained from US FDA report.[41]

e

Many low-dose and terminal-phase samples had concentrations below the limit of quantitation.

f

Pharmacokinetic data are for first and twelfth doses combined.

3D = three doses at 48-hour intervals; AUC = area under the plasma concentration-time curve; CL = clearance; Cmax = maximum plasma concentration; SD = single dose; tiw = three times per week; t1/2γ = terminal elimination half-life; VSS = apparent volume of distribution at steady state; * indicates significant difference between different dose groups (p = 0.0007).

3.2 Metabolism and Excretion

Paricalcitol is metabolised through the CYP24 pathway in cultured MG-63 cells at a rate similar to that of calcitriol, with both drugs effectively upregulating CYP24 mRNA levels.[21] In 0- to 48-hour urine and 24- to 168-hour faeces samples, only 5.7% of an intravenous dose of tritiated paricalcitol was excreted unchanged in healthy volunteers.[41] Paricalcitol and metabolites undergo biphasic elimination, primarily by biliary excretion,[41] in both healthy volunteers[43] and patients undergoing haemodialysis.[44] In healthy volunteers, paricalcitol elimination was rapid, with a terminal elimination half-life (t1/2γ) of ≤7.3 hours.[41] In patients undergoing haemodialysis, elimination was relatively slow with a clearance of 0.58–0.91 L/h and a t1/2γ between 11 and 32 hours (table II), suggesting a proportion of paricalcitol is eliminated through a renal route.[44] However, disposition and excretion studies conducted in healthy male volunteers indicated that paricalcitol is eliminated primarily in faeces (73.7%) with only 15.8% eliminated in urine.[40] In a second © 2005 Adis Data Information BV. All rights reserved.

group of haemodialysis patients, the t1/2γ, based on extrapolated mean concentrations before and after dialysis, was 14.6 hours, implying prolonged plasma residence.[42] In these patients, clearance did not appear to be altered by haemodialysis, indicating that paricalcitol may be administered at any time during haemodialysis.[42] 4. Therapeutic Efficacy The efficacy of intravenous paricalcitol in the treatment of secondary hyperparathyroidism has been evaluated in adult patients with chronic renal failure undergoing haemodialysis in several randomised, double-blind, multicentre trials.[41,45-47] These trials were placebo[46,47] or active-comparator[41,45] controlled. One of these studies is unpublished but was reported in an FDA document;[41] additional data from this[41] and another FDA report[48] also supplemented two of the other studies.[45,47] One placebo-controlled trial was a doseranging study[46] and three were reported as pooled data.[47] Additional active-comparator data were reported in two large retrospective analyses.[1,49] Data Drugs 2005; 65 (4)

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from a long-term noncomparative 13-month trial[50] and a 16-month trial in calcitriol-resistant patients[51] are also reviewed. The effects of switching from calcitriol to paricalcitol have been evaluated in 4week[52] and 6-month[53] observational studies. Some data from a study in children and young adults have been reported.[19,54,55] Two studies[53,54] are only available as abstracts. Patients were admitted to the various trials with differing criteria for serum PTH levels. Patients previously receiving calcitriol could have serum PTH levels as low as 250 pg/mL;[41,45] however, in most trials the threshold for serum PTH was ≥300[41,45,46,50,54] or ≥400 pg/mL.[47,52] In a study of paricalcitol therapy in calcitriol-resistant patients the serum PTH entry level was ≥600 pg/mL.[51] Other entry criteria included a serum calcium level ranging from 6.8 to 11.5 mg/dL,[19,41,45-47,52] a calcium-phosphorus product (Ca × P) ≤70[19,50] or ≤75 (mg/dL)2;[41,45,47,52] and a serum inorganic phosphate level ≤6 mg/dL.[46] Paricalcitol or calcitriol was generally administered as an intravenous bolus injection during thriceweekly dialysis[46,47,51,52] (see table III for dosage and design details). In three trials, patients undergoing therapy with calcitriol were switched to paricalcitol at calcitriol : paricalcitol dose conversion ratios of 1 : 4[51,52] and/or 1 : 3.[51,53] Doses of either paricalcitol or calcitriol were increased until ≥30%[47,52,54] or ≥50%[41,45] reductions in serum PTH levels had been achieved, whereupon the dose was maintained constant until completion of the trial, with the exception of one of the long-term noncomparative trials where the dose was gradually reduced as serum intact PTH (iPTH) levels declined, so that the dose at 16 months was ≈3-fold lower than that used at entry.[51] In other trials dose reductions occurred if serum PTH levels decreased to 75 (mg/ dL)2;[41,45,47,51,52] if serum calcium levels were >11.5 mg/dL;[41,45,47,51,52] or if serum phosphorus levels were >7.5 mg/dL.[51] Although the description of endpoints for some of the trials was ambiguous,[45,47] reference to the US FDA reports[41,48] clarifies the following primary endpoints: a decrease in serum iPTH level of ≥30% from maximum baseline on one[46,47] or more occasions;[47,54] and tolerability (the combined incidence © 2005 Adis Data Information BV. All rights reserved.

Robinson & Scott

of an episode of elevated serum calcium levels [≥11.5 mg/dL] and/or an episode of Ca × P ≥75 [mg/ dL]2) in calcitriol-controlled trials[41,45] which is discussed in section 5. Except for one trial,[47] all analyses were based on the intent-to-treat population.[41,45,46] 4.1 In Adult Patients 4.1.1 Versus Placebo

Over a range of doses (0.04–0.24 μg/kg), paricalcitol recipients experienced a dose-dependent reduction in mean serum iPTH levels from baseline after 4 weeks, with the majority of patients achieving at least a 30% reduction (table III).[46] In a pooled analysis of three identical, doubleblind multicentre trials, mean serum iPTH levels were significantly reduced from baseline in paricalcitol but not placebo recipients after 12 weeks (table III).[47] The majority of paricalcitol recipients achieved at least a 30% reduction in mean serum iPTH levels, whereas few placebo recipients did (table III).[47] Paricalcitol treatment also significantly reduced serum levels of alkaline phosphatase, an indicator of bone remodelling, from 148 U/L at baseline to 101 U/L after 12 weeks (p < 0.001), whereas in placebo-treated patients no change was observed (120 vs 130 U/L).[47] In both reports of placebo-controlled trials, paricalcitol induced very little change in mean serum phosphorus levels, and a small but significant (p < 0.02[47] and p < 0.001[46] vs baseline) rise in mean serum calcium levels.[46,47] In one of the trials[46] this was matched by a similar increase in placebo recipients, while in the pooled analysis,[47] mean serum calcium levels increased from 9.24 mg/ dL at baseline to 9.56 mg/dL at study end but remained within the normal range (8.5–10.5 mg/dL) in paricalcitol recipients. 4.1.2 Versus Calcitriol Prospective Trials

There was no significant difference between paricalcitol and calcitriol treatment in the proportion of patients achieving a ≥50% reduction in mean serum iPTH[41] or serum PTH[45] levels (table III). There was also no significant between-group difference in serum iPTH [41] or serum PTH[45] levels at study end, Drugs 2005; 65 (4)

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Table III. Efficacy of intravenous paricalcitol (PAR) in the treatment of secondary hyperparathyroidism in adult patients (pts) with chronic renal failure undergoing haemodialysis. Summary of randomised, double-blind, multicentre trials. Except for one trial,[47] all analyses were intent-to-treat[41,45,46] Study (duration in weeks)

No. of Treatment pts (μg/kg tiw)

Mean percentage decrease in serum iPTH[41,46,47] or PTH[45] at endpoint [baseline; pg/mL]

Percentage of pts achieving ≥30% reduction in serum iPTH for 1[46] or 4 consecutive weeks[47]

Percentage of pts achieving ≥50%a reduction in serum iPTH[41] or PTH[45] level

Mean percentage increase in serum calcium level [baseline; mg/dL]

Mean percentage change in serum phosphorus level [baseline; mg/dL]

Mean percentage increase in Ca × P [baseline; (mg/dL)2]

Versus placebo (PLA) Llach et al.[46] (4)

Martin et al.[47]f (12)

6

PAR 0.04

11b [691c]

67d

4

PAR 0.08

28b

25d

6

PAR 0.16

68b

83d

6

PAR 0.24

76b

83d

0b

13

PLA

40

PAR 0.04g,h 49†† [795]

[728]

38

PLA

99

PAR 0.04g,k 54 [670]

98

CAL 0.01l

2†† [9.25]e –10 [5.4]e

15d

3†† [8.95]e

68*d

4† [9.24]

8d

0 [9.06]

8 [5.86] –9 [6.00]

57

12 [9.00]

25 [5.65]

53

12 [9.00]

25 [5.80]

30 [61]

62

12 [9.00]

15 [5.82]

15 [53]

13 [680]

9 [6.00]e

Versus calcitriol (CAL) Lutwak et al.[41]i,j (24) Sprague et al.[45]m,j (32)

130

57 [620]

PAR 0.04g,k 60b [648]

35 [64]

a

42b [675] 54 17 [8.90] 13 [5.80] 23 [52] A ≥50% reduction was chosen to provide a reference point to gauge potential hypercalcaemic and hyperphosphataemic activity.

b

Estimated from a graph.

c

For all PAR recipients in this study.

d

Primary endpoint.

e

Pooled data for all doses estimated from a graph.

f

Pooled data from three trials. Data also obtained from US FDA report.[48]

g

Dose increased by 0.04 μg/kg at 2-[47] or 4-week[41,45] intervals based on efficacy and tolerability.

h

Median dose 0.12 μg/kg.

133

CAL 0.01l

i

Unpublished study, data obtained from US FDA report.[41]

j

Primary endpoint in this trial was tolerability.

k

Maximum dose 0.20 μg/kg.

l

Dose increased by 0.01 μg/kg at 4-week intervals based on efficacy and tolerability.[41,45]

m Data also obtained from US FDA report.[41] Ca × P = calcium-phosphorus product; (i)PTH = (intact) parathyroid hormone; tiw = three times weekly; * p < 0.001 vs PLA; †† p < 0.001 vs baseline.

although at individual time points during both of the studies, levels were significantly lower in paricalcitol-treated patients (p-values not reported).[41] In one of the studies,[45] but not the other,[41] serum PTH levels were reduced more rapidly with paricalcitol than calcitriol treatment, with a significantly shorter time to the first period of four consecutive reductions from baseline in serum iPTH of ≥50% (median 87 vs 108 days; p = 0.025). It should be noted; however, that a rapid decline in serum PTH © 2005 Adis Data Information BV. All rights reserved.

†

p < 0.02,

levels has been associated with a higher incidence of elevated serum calcium levels[51] (see section 5). Mean serum iPTH[41] or serum PTH[45] levels had decreased into the optimum therapeutic range (72 [mg/dL]2) [see section 5].[55] Ten of the paricalcitol and two of the placebo recipients completed the trial, with 70% of the placebo withdrawals occurring because of elevation of serum iPTH levels above 700 pg/mL after 4 weeks of treatment.[55] A last-observation-carried-forward analysis indicated there was no significant between-group difference in the proportion of patients achieving the primary endpoint (two consecutive ≥30% reduction in serum iPTH); achieved by 9 of 15 (60%) paricalcitol and 3 of 14 (21%) placebo recipients (95% CI for the difference –1, 63).[55] However, there was a significant between-group difference in the change in mean serum iPTH level from baseline (–164 vs 238 pg/mL in the placebo arm; p = 0.03)[55] [baseline mean serum iPTH levels of 841 and 740 pg/mL].[19] In paricalcitol recipients, mean serum levels of calcium at baseline and after 12 weeks of treatment were 9.5 and 9.5 mg/dL, while serum phosphorus levels were 5.4 and 5.3 mg/dL and Ca × P values were 51.3 and 50.0 (mg/dL)2 [p-values not reported].[54] In calcitriol recipients, serum calcium levels were 8.7 and 9.2 mg/dL, serum phosphorus levels were 6.4 and 6.6 mg/dL and Ca × P values were 54.5 and 59.2 (mg/dL)2 [p-values not reported].[54] 5. Tolerability In general, paricalcitol was well tolerated by both adults[41,45-47,50,51] and children[54,55] participating in trials discussed in section 4. The most serious ad© 2005 Adis Data Information BV. All rights reserved.

verse events associated with vitamin D therapy are an increased incidence of hypercalcaemia or hyperphosphataemia and/or Ca × P;[57] indeed, the combined incidence of an episode of elevated serum calcium levels and/or an episode of elevated Ca × P was a primary endpoint in the active comparator trials.[41,45] In placebo-controlled trials in adults, the incidence of single episodes of elevated serum calcium levels in paricalcitol-treated patients was low (5%[47] and 18%;[46] table V); no episodes occurred in placebo recipients in one trial[47] and the incidence was not reported in the other.[46] In the 4-week trial[46] the episodes occurred in paricalcitol recipients who had experienced 48–98% decreases in serum iPTH levels, much greater than the targeted 30% reductions, and may reflect decreased ability to buffer serum calcium as serum PTH approaches normal levels.[46] Other treatment-emergent adverse events reported during paricalcitol or placebo treatment in adults included nausea (21% vs 16%), vomiting (13% vs 8%) and oedema (11% vs 0%).[19] The effect of paricalcitol compared with calcitriol on the induction of hypercalcaemia, hyperphosphataemia and/or elevated Ca × P was equivocal.[41,45] In the published trial,[45] no difference was observed between paricalcitol and calcitriol groups in the primary endpoint, the combined incidence of an episode of elevated serum calcium levels and/or an episode of elevated Ca × P (table V), nor did the incidence of the individual parameters differ significantly between groups (table V). However, in the unpublished trial,[41] both the combined incidence of elevated calcium and/or Ca × P and the individual incidence of elevated Ca × P differed significantly between treatment groups (table V). In contrast, periods of prolonged hypercalcaemia or elevated Ca × P (at least two consecutive hypercalcaemic and/or four consecutive Ca × P >75 [mg/dL]2 samples) were less common in paricalcitol than in calcitriol recipients in one trial (18% vs 33%; p = 0.008)[45] and did not differ in the other (31.6% vs 32.4%).[41] In longer-term noncomparative studies, 10%[50] and 22%[51] of patients receiving paricalcitol experienced elevated serum calcium levels while 5%[50] and 17%[51] experienced elevated serum phosphorus Drugs 2005; 65 (4)

Paricalcitol in Secondary Hyperparathyroidism

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levels (table V). During the 16-month trial, hypercalcaemia developed in 7 of the first 14 patients enrolled.[51] In these patients, where the calcitriol : paricalcitol dose conversion ratio was 1 : 4, the reduction in serum iPTH level was very rapid, from a mean of 1008 to 194 pg/mL in 2 months, and may have been responsible for the development of hypercalcaemia. As a result, the starting calcitriol : paricalcitol dose conversion ratio was reduced from 1 : 4 to 1 : 3 for the 23 patients enrolled subsequently, in whom a more gradual reduction in serum iPTH levels, from a mean of 836 to 341 pg/mL at 2 months, and only one episode of mildly elevated serum calcium (10.7 mg/dL), were observed. An initial dosing strategy based on baseline serum iPTH level rather than bodyweight, resulted in a more rapid reduction in serum iPTH levels of ≥30% (31 vs 45 days; p = 0.0306) without affecting the incidence of hypercalcaemia or Ca × P >75 (mg/

dL)2 in a 12-week randomised, double-blind, double-dummy trial in 125 patients.[58] In children and young adults, the frequency of adverse events did not differ between treatment groups, with 67% of paricalcitol recipients versus 43% of placebo recipients reporting a total of 17 versus 15 adverse events.[55] There was no statistically significant difference between paricalcitoland placebo-treated patients in the incidence of elevated serum levels of calcium, phosphorus or Ca × P (table V).[55] Serious adverse events requiring hospitalisation were experienced by three patients receiving paricalcitol (clotted venous access) and three receiving placebo (post-arteriovenous graft bleeding, cellulitis, depression and sepsis).[55] 6. Dosage and Administration Paricalcitol is approved in the US[19] and in most European nations, including Spain[59] and the UK,[60] for use in adults in the prevention and treatment of

Table V. Effect of intravenous paricalcitol (PAR) three times per week on the incidence of single episodes of elevated serum levels of calcium (>10.3[54] or >10.5[46,51] or normalised >11.5[41,45,47,50] mg/dL), phosphorus (>7.5 mg/dL[51,54] or not specified[50,54]), calcium-phosphorus product (Ca × P ) [≥75 [41,45] or >70[46] (mg/dL)2] and the combined incidence of an episode of elevated serum calcium and/or an episode of elevated Ca × P, during treatment of secondary hyperparathyroidism in patients (pts) with chronic renal failure undergoing haemodialysis. Trials were in adults unless stated otherwise Study

No. of pts

Treatment (duration)

Elevated calcium (% of pts)

Elevated phosphorus (% of pts)

Elevated Ca × P (% of pts)

Elevated calcium and/or Ca × P (% of pts)

Versus placebo (PLA) Llach et al.[46]a Martin et al.[47]b

22

PAR (4wk)

18

36

13

PLA (4wk)

NR

15

40

PAR (12wk)

5

25

48

PLA (12wk)

0

5

Versus calcitriol (CAL) Lutwak[41]b,c Sprague et al.[45]b,c

99

PAR (24wk)

28

74*

79*

98

CAL (24wk)

17

59

65

130

PAR (32wk)

23

57

68

133

CAL (32wk)

23

59

64

Children and young adults Melnick et al.[54,55]

15

PAR (12wk)

23

75

40

15

PLA (12wk)

31

43

14

PAR (13mo)

10

5

22

17

a

37 PAR (16mo) All dosage levels of paricalcitol combined.

b

Data also obtained from US FDA report.[48]

c

The combined incidence of elevated serum calcium levels and/or Ca × P was the primary endpoint.

Longer-term noncomparative studies Lindberg et al.[50]

164

Llach et al.[51]

NR = not reported; * p < 0.05 vs calcitriol.

© 2005 Adis Data Information BV. All rights reserved.

Drugs 2005; 65 (4)

572

secondary hyperparathyroidism associated with chronic renal failure. In the US it is also approved for use in paediatric patients[19] based on a study in patients aged 5–19 years. The recommended initial dosage of paricalcitol is 0.04–0.1 μg/kg administered as a bolus, no more frequently than on alternate days, at any time during dialysis.[19] Doses as high as 0.24 μg/kg (16.8μg) have been safely administered. The dosage may be increased by 2–4μg at 2- to 4-week intervals. Serum calcium and phosphorus levels should be monitored twice weekly during dose adjustment and dosage should be reduced or interrupted if serum calcium becomes elevated or Ca × P exceeds 75 (mg/dL)2. The dosage may need to be reduced as serum PTH levels decrease during therapy.[19] Paricalcitol should not be administered to patients with evidence of vitamin D toxicity or hypercalcaemia.[19] Local prescribing information should be consulted for dosage reduction guidelines, recommendations for special populations, contraindications and precautions. 7. Place of Paricalcitol in the Management of Secondary Hyperparathyroidism General treatment guidelines for chronic kidney disease aim to slow the loss of kidney function, prevent and treat complications of decreased kidney function and replace kidney function by dialysis and transplantation.[9] The loss of functional renal mass in the early stages of renal insufficiency results in the development of secondary hyperparathyroidism characterised by reduced serum levels of calcitriol and calcium and elevated serum levels of PTH and phosphorus (section 1). Patients experience highturnover bone disease (osteitis fibrosa cystica) and soft tissue calcification, significantly increasing the rate of cardiovascular disease and relative mortality risk.[2,13] Re-evaluation of the ideal target for serum levels of iPTH, calcium, phosphorus and Ca × P was called for[61] and new target levels recommended[9] in order to minimise soft tissue calcification, although recent data suggest that even within the normal range of serum calcium levels (8.5–10.5 mg/dL[62]) relative risk of death is greater at higher calcium levels.[14] © 2005 Adis Data Information BV. All rights reserved.

Robinson & Scott

The increased incidence of adynamic bone disease[63] and loss of sensitivity to vitamin D levels in patients with secondary hyperparathyroidism, due to reduced VDR density,[64] particularly in nodular hyperplasia of the parathyroid gland,[65] suggest that the recommended target serum iPTH level (measured by first generation immunoassay) should be 2to 4-fold higher than normal (100–300 pg/mL).[66] Initial therapy in patients with mild-to-moderate renal insufficiency (stages 2 and 3, glomerular filtration rate [GFR] 60–89 and 30–59 mL/min, respectively) should consist of dietary phosphorus restriction and phosphate binders.[7] The initiation of vitamin D therapy early in disease progression, when parathyroid glands exhibit diffuse hyperplasia,[67] may prevent the development of nodular hyperplasia[65] and loss of VDR density[64] which leads to progressive increases in serum PTH. In patients with chronic renal failure who have fully developed secondary hyperparathyroidism, a comprehensive management plan may include a restricted intake of calcium and phosphorus, the use of cationic or non-cationic phosphate binders and the use of active vitamin D preparations to reduce serum iPTH (for specific recommendations see the National Kidney Foundation Kidney Disease Outcomes Quality Initiative[9]). Subtotal parathyroidectomy or total parathyroidectomy with parathyroid tissue autotransplantation may be necessary in patients with severe persistent hyperparathyroidism (serum iPTH >800 pg/mL) associated with hypercalcaemia and/or hyperphosphataemia that are refractory to medical therapy.[9] However, it has been suggested that such surgical intervention leads invariably to low-turnover bone disease.[68] In paediatric patients with renal failure, the prime treatment objective is to protect the developing skeleton, allowing normal growth while preventing parathyroid hyperplasia.[15] Management should aim to correct hypocalcaemia and maintain normal serum phosphorus levels through dietary phosphorus restriction (which has been used to increase serum calcitriol and decrease serum PTH levels in children with chronic renal failure[69]) or with phosphatebinding agents, while metabolic acidosis and serum iPTH levels should be normalised (reviewed by Sanchez[15]). Early treatment with oral vitamin D has reportedly been effective in reducing serum PTH Drugs 2005; 65 (4)

Paricalcitol in Secondary Hyperparathyroidism

levels, improving linear growth, correcting hypocalcaemia and reducing skeletal lesions (see Sanchez[15]). Treatment of secondary hyperparathyroidism with intravenous calcitriol reduces serum PTH, but increased calcitriol often leads to the development of hypercalcaemia and further hyperphosphataemia (see figure 1 and section 2). Hypercalcaemia may also be exacerbated by the use of calcium-containing phosphate-binding agents.[18] Curiously, dialysis patients may also suffer from low-turnover bone diseases (adynamic bone disease and osteomalacia) resulting from hypercalcaemic suppression of PTH secretion during vitamin D therapy,[70] resistance to PTH through the down-regulation of VDR[64] and/or the accumulation of aluminium from aluminiumbased phosphate binders.[64] Trials of the calcimimetic cinacalcet (recently approved in the US and Europe[71]), which activates the calcium-sensing receptor to suppress PTH secretion,[72] suggest that the use of cinacalcet in combination with vitamin D therapy may be advantageous. It rapidly suppresses PTH secretion while decreasing serum calcium levels and Ca × P in patients with uncontrolled secondary hyperparathyroidism also receiving vitamin D therapy.[73] The position of calcimimetics in relation to traditional therapies remains to be determined (see recent review by Barman Balfour and Scott[74]). Other vitamin D analogues used in the treatment of secondary hyperparathyroidism include oral and intravenous 1α-hydroxyvitamin D2 (doxercalciferol).[75,76] These vitamin D analogues, like paricalcitol, are effective in reducing serum iPTH levels while inducing modest increases in serum calcium and phosphorus levels;[75,76] however, comparative trials with an established therapy (such as calcitriol) do not appear to have been performed with these agents. In an attempt to find a better calcitriol analogue, a variety of vitamin D compounds were screened and paricalcitol was identified as having up to one-third of the potency of calcitriol in decreasing PTH secretion but one-tenth the hypercalcaemic and hyperphosphataemic effect in animal models (section 2).[68] Because of this wider therapeutic window, clinical trials were initiated to study its use in secondary hyperparathyroidism. © 2005 Adis Data Information BV. All rights reserved.

573

In patients with secondary hyperparathyroidism, paricalcitol was found to have similar efficacy to calcitriol in inhibiting PTH secretion and reducing serum alkaline phosphatase levels in short-term clinical trials (24 and 32 weeks duration), while inducing similar serum calcium and phosphorus accumulation (section 4.1.2). In longer-term retrospective analyses (35 and 36 months duration), patients treated with paricalcitol had a significant survival advantage and were also less likely to be admitted to hospital and spent less time in hospital than patients receiving calcitriol (section 4.1.2). As a consequence, the use of paricalcitol may be associated with a reduction in hospitalisation costs (section 4.1.2). Limited data also indicate that the drug is effective in children and young adults aged 5–19 years (section 4.2). Paricalcitol was generally well tolerated in both adults and children participating in clinical trials (section 5), in which it was as well tolerated as calcitriol in terms of the incidence of prolonged episodes of hypercalcaemia and/or elevated Ca × P. Further longer-term trials with larger numbers of patients are needed to satisfy concerns about the long-term safety of paricalcitol therapy and in particular its effects on kidney function. Evidence of a deterioration in kidney function with calcitriol is equivocal, although the development of hypercalcaemia during vitamin D treatment is associated with transient or long-lasting loss of kidney function.[9] Although paricalcitol increases the susceptibility of proximal tubular cells to oxidative damage in vitro (section 2.4), recent trials of an oral formulation of paricalcitol for 24 weeks revealed no significant deterioration in GFR when compared with placebo treatment.[77] Bone biopsy evaluations to determine whether the control of serum PTH levels obtained with paricalcitol is reflected in improvements in bone mineral content and/or in histological features of hyperparathyroid bone disease are necessary, as reliance on reduced serum PTH levels as the primary measure of treatment efficacy may be misleading. While paricalcitol is approved for both the prevention and treatment of secondary hyperparathyroidism, its effectiveness in the prevention of parathyroid hyperplasia, nodular hyperplasia and loss of VDR density has yet to be examined. Further research on the Drugs 2005; 65 (4)

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Robinson & Scott

optimal dosing regimen is also required, including determination of an optimal regimen for parathyroid versus bone therapy, assessment of the advantages and/or disadvantages of pulse dosing with paricalcitol and examination of the daily and/or thriceweekly use of an oral formulation of paricalcitol.[78] Trials of oral paricalcitol versus other low-dose oral vitamin D formulations and intravenous calcitriol and paricalcitol would be useful in assessing cost and compliance issues. An oral formulation may also simplify vitamin D therapy in patients treated with continuous ambulatory peritoneal dialysis and promote early intervention in chronic renal failure to minimise nodular hyperplasia of the parathyroid gland. In conclusion, paricalcitol effectively reduced elevated serum PTH levels and was generally well tolerated in children, adolescents, and adults with secondary hyperparathyroidism associated with chronic renal failure. In well designed clinical trials, paricalcitol was as effective as calcitriol and at least as well tolerated in terms of the incidence of prolonged hypercalcaemia and/or hyperphosphataemia. Thus, paricalcitol is an effective alternative to calcitriol in the management of secondary hyperparathyroidism in adults and children with chronic renal failure.

11. 12. 13.

14. 15. 16. 17.

18. 19. 20. 21.

22.

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30.

31. 32. 33.

34.

35. 36.

37.

38.

39.

40. 41. 42. 43.

44.

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Correspondence: Dean M. Robinson, Adis International Ltd, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 1311, New Zealand. E-mail: [email protected]

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