ORIGINAL RESEARCH ARTICLE

Clin Pharmacokinet 2005; 44 (5): 509-516 0312-5963/05/0005-0509/$34.95/0 © 2005 Adis Data Information BV. All rights reserved.

No Effect of Renal Function or Dialysis on Pharmacokinetics of Cinacalcet (Sensipar®/Mimpara®) Desmond Padhi,1 Robert Z. Harris,2 Margaret Salfi3 and John T. Sullivan1 1 2 3

Department of Early Development, Amgen Inc., Thousand Oaks, California, USA Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, California, USA Department of Biostatistics, Amgen Inc., Thousand Oaks, California, USA

Abstract

Objective: Cinacalcet (cinacalcet HCl; Sensipar®/Mimpara®) is a calcimimetic that is a treatment for secondary hyperparathyroidism in patients with renal failure. The objective of this study was to assess the effects of renal function and dialysis on the pharmacokinetics and pharmacodynamics of cinacalcet. Methods: Two open-label, single-dose (75mg) studies of cinacalcet were performed: study 1 examined 36 subjects who had renal function ranging from normal to requiring haemodialysis, and study 2 examined ten subjects who were receiving continuous ambulatory peritoneal dialysis. Cinacalcet plasma concentrations were determined using a liquid chromatography-mass spectrometry/mass spectrometry assay. Cinacalcet pharmacokinetics were assessed using noncompartmental analyses. Results: Following single-dose administration of cinacalcet, there was no evidence of increasing exposure with increasing degree of renal impairment, and the pharmacokinetic profile was similar for all subjects regardless of whether they were receiving haemodialysis (no difference on dialysis or nondialysis days detected) or peritoneal dialysis. Protein binding of cinacalcet, determined in study 1 only, was similar in all groups and the level of renal function did not affect the pharmacodynamics (as determined by intact parathyroid hormone and calcium levels). No serious adverse events occurred during either study. Conclusion: The degree of renal impairment and mode of dialysis do not affect the pharmacokinetics or pharmacodynamics of cinacalcet. Therefore, the dose of cinacalcet does not need to be altered for degree of renal impairment or dialysis modality.

Cinacalcet (cinacalcet HCl; Sensipar®/ Mimpara®, Amgen Inc., Thousand Oaks, CA, USA), a calcimimetic agent, acts as a positive allosteric modulator of the calcium-sensing receptor (CaR)[1] expressed by parathyroid cells.[2] By in-

creasing the sensitivity of the CaR to activation by extracellular calcium, cinacalcet decreases parathyroid hormone (PTH) release.[1] When subjects with chronic kidney disease (CKD) and secondary hyperparathyroidism were treated with cinacalcet,

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Table I. Baseline characteristics and laboratory values of study subjects Parameter

Renal function group normal (n = 12)

mild (n = 6)

moderate (n = 6)

severe (n = 6)

ESRD (HD; n = 6)

ESRD (CAPD; n = 10)

Sex [n (%)] Men

8 (66)

5 (83)

3 (50)

3 (50)

5 (83)

7 (70)

Women

4 (33)

1 (16)

3 (50)

3 (50)

1 (16)

3 (30)

White

10 (83)

5 (83)

4 (66)

3 (50)

1 (16)

1 (10)

Black

1 (8)

1 (16)

2 (33)

2 (33)

4 (66)

9 (90)

Hispanic

1 (8)

0 (0)

0 (0)

1 (16)

1 (16)

0 (0)

Race [n (%)]

Age (y) Median (range)

59.0 (42–69)

60.0 (49–70)

64.5 (49–69)

60.5 (47–65)

51.5 (30–71)

45.5 (21–63)

90.5 (65–109)

85.2 (72–95)

95.5 (69–110)

82.5 (70–114)

76.0 (48–100)

85.6 (61–133)

28.8 (25.5–37.6)

30.2 (23.1–36.4)

29.5 (23.1–32.2)

29.8 (22.0–37.4)

25.9 (17.5–29.9)

28.1 (21.4–42.9)

45.0 (34–66)b

20.0 (4–29)

Weight (kg) Median (range) BMI

(kg/m2)

Median (range) CLCR (mL/min)a

Median (range) 101.0 (83–188) 65.5 (55–76) a CLCR was not calculated for subjects with ESRD. b

One subject was enrolled in the moderate group based on historical, rather than baseline, CLCR values because over-collection of urine occurred for the baseline evaluation.

BMI = body mass index; CAPD = continuous ambulatory peritoneal dialysis; CLCR = creatinine clearance; ESRD = end-stage renal disease; HD = haemodialysis.

reductions in the levels of plasma PTH, serum calcium, serum phosphorus and the calcium-times-phosphorus product (Ca × P) were observed.[3-6] Controlling these parameters is clinically important as they are associated with negative outcomes (e.g. renal osteodystrophy, vascular calcification, cardiovascular risk and mortality risk).[7-12] Such abnormalities may develop in the early stages of CKD[13] and, therefore, treatment for secondary hyperparathyroidism may be beneficial for patients with different degrees of renal impairment. Although cinacalcet is cleared predominantly by oxidative hepatic metabolism and minimally by renal mechanisms, renal impairment can cause changes in absorption, hepatic metabolism, plasma protein binding and distribution that could potentially impact its pharmacokinetic and pharmacodynamic characteristics.[14] For this reason, the pharmacokinetics and pharmacodynamics of cinacalcet were evaluated in subjects along the continuum of renal function from normal to end-stage renal disease (ESRD). © 2005 Adis Data Information BV. All rights reserved.

Methods Study Design

Two open-label, single-dose studies were conducted to characterise the pharmacokinetics and pharmacodynamics of cinacalcet in subjects with varying degrees of renal function. The levels of renal impairment for subjects not receiving dialysis were categorised based on the creatinine clearance (CLCR) ranges outlined in the regulatory guidelines:[15] healthy/normal, CLCR >80 mL/min; mild CKD, CLCR 50–80 mL/min; moderate CKD, CLCR 30–50 mL/min; and severe CKD, <30 mL/min. CLCR was calculated according to section 1: CLCR = (urine creatinine/serum creatinine) × (urine volume [mL]/time [min]) × (1.73 [m2])/(body surface area) where time is 1440 minutes. Study 1 included healthy subjects, subjects with CKD who were not receiving dialysis and subjects Clin Pharmacokinet 2005; 44 (5)

Pharmacokinetics of Cinacalcet

511

with ESRD who were receiving haemodialysis. Study 2 included subjects with ESRD who had been receiving continuous ambulatory peritoneal dialysis (CAPD) for at least 1 month. Both studies were approved by the Institutional Review Boards (IRBs) used by each of the study sites: the Biomedical Research Institute of America IRB for the Orlando Clinical Research Center, Orlando, FL, USA; the internal IRB for the Clinical Research Center, New Orleans, LA, USA; and the Research Consultants’ Review Committee for Radiant Research, Austin, TX, USA. All subjects provided written informed consent before participation. Cinacalcet was administered as a single 75mg oral dose (three 25mg tablets). Patients on haemodialysis received the same dose on two occasions: the first on a nondialysis day, and the second after at least a 2-week washout period, 3 hours before initiation of haemodialysis. ESRD subjects on CAPD received the drug on one occasion that was within 10 minutes of initiating a dialysate exchange. No other medications except paracetamol (acetaminophen) for healthy subjects, or paracetamol and established therapy for subjects with CKD or ESRD, were to be taken within 2 weeks of cinacalcet administration, unless it was a medical emergency. In addition, administration of medications used to manage renal

failure was to be separated by 4 hours where possible. Pharmacokinetics and Pharmacodynamics

Plasma concentrations of cinacalcet were measured before administration and up to 72 hours after dosing. For subjects receiving haemodialysis, venous samples were obtained on the dialysis day before dosing, several times during the 3 hours before haemodialysis was initiated and then at frequent intervals from 4–72 hours after administration. Arterial samples were obtained via arteriovenous fistulas at the beginning of dialysis and several times during haemodialysis. Cinacalcet plasma concentrations were determined using a liquid chromatography-mass spectrometry/mass spectrometry assay with a lower limit of quantitation of 0.1 ng/mL. The pharmacokinetic parameters assessed included area under the plasma concentration-time curve from time zero to the last measurable concentration after study drug administration (AUCt), area under the plasma concentration-time curve from time zero to infinity after study drug administration (AUC∞), observed maximum plasma concentration (Cmax), time to observed peak plasma concentration (tmax), oral clearance (CL/F) and elimination halflife (t1/2β). Pharmacokinetic parameters were de-

Table II. Mean (SD) single-dose pharmacokinetic parameters and level of renal function Pharmacokinetic

Renal function group

parametera

normal

mild

moderate

severe

ESRD (haemodialysis)

ESRD

(n = 12)

(n = 6)

(n = 6)

(n = 6)

nondialysis day dialysis day (n = 6) (n = 6)

(CAPD; n = 10)

20.6 (14.7)

25.0 (23.0)

Cmax (ng/mL)

26.6 (9.4)

40.1 (18.9)

14.8 (8.5)

tmax (h)b

6.0 (3.0–6.0)

6.0 (2.5–8.0)

5.0 (2.0–8.0) 6.0 (4.0–8.0) 2.3 (1.0–6.0)

30.1 (30.2)

22.9 (14.9)

3.5 (3.0–4.3)

3.3 (1.0–8.0)

AUCt (ng • h/mL)

272 (128)

423 (255)

176 (111)

286 (224)

282 (241)

281 (284)

228 (172)

AUC∞ (ng • h/mL)

296 (143)

447 (264)

200 (126)

346 (302)

303 (254)

302 (298)

258 (187)

t1/2 (h)

30.4 (6.5)

23.1 (13.8)

35.4 (9.6)

33.6 (14.1)

23.5 (10.7)

24.7 (7.1)

40.9 (23.1)

CL/F (L/h)

314 (148)

231 (140)

543 (348)

359 (198)

472 (418)

532 (457)

394 (199)

Mean (SD) % protein bound

94.7 (2.2)

94.7 (1.9)

92.7 (2.9)

93.1 (1.6)

95.2 (1.4)

a

Parameters are based on analysis of concentration-time values through 72 hours.

b

tmax is presented as median (range).

AUCt = area under the plasma concentration-time curve from time zero to the last measurable concentration after study drug administration; AUC∞ = area under the plasma concentration-time curve from time zero to infinity after study drug administration; CAPD = continuous ambulatory peritoneal dialysis; CL/F = oral clearance; Cmax = observed maximum plasma concentration; ESRD = end-stage renal disease; t1/2 = terminal phase half-life; tmax = time to observed peak concentration.

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1000

Individual Mean

AUC∞ (ng • h/mL)

800

600

400

200

(n CA = PD 10 )

ly si H (n s da D = y 6)

ia D

N

on

di

al

ys H i (n s da D = y 6)

Se (n ve = re 6)

od (n era = te 6)

M

(n Mi = ld 6)

N (n orm = 12 al )

0

Renal function group Fig. 1. Area under the plasma concentration-time curve from time zero to infinity after study drug administration (AUC∞) in subjects with normal renal function vs subjects with various degrees of renal impairment. AUC∞ calculation was based on analysis of concentration-time values through 72 hours. CAPD = continuous ambulatory peritoneal dialysis; HD = haemodialysis.

rived using noncompartmental methods (WinNonlin v. 3.1, Pharsight Corp., Mountain View, CA, USA). Determination of half-life (t1/2) [data not shown] was performed by reviewing a semi-log plot. A linear regression of the log-transformed terminal data points versus time was used to estimate β, and t1/2 was calculated as 0.693/β. AUCt was calculated by the linear trapezoidal rule. AUC∞ was calculated by dividing the predicted concentration at the time of the last measurable concentration by β. AUC∞ was calculated by determining the summation of AUCt and AUCt–∞. CL/F was calculated as dose/ AUC∞. Bioequivalence comparisons were not provided for the pharmacokinetic parameters: a descriptive approach was considered more meaningful, given the small sample size and parallel-design of the study. Protein binding and plasma intact parathyroid hormone (iPTH) concentrations were also assessed. Protein binding was determined in study 1 only and was assessed by ultracentrifugation. Plasma iPTH concentrations were determined using a double© 2005 Adis Data Information BV. All rights reserved.

antibody immunoradiometric assay for the intact hormone (Nichols Institute Diagnostics, San Juan Capistrano, CA, USA), and were taken before dosing and at 2, 4, 8, 12, 24, 48 and 72 hours after dosing. Changes from baseline were assessed descriptively. Results

Subjects

A total of 46 subjects (12 healthy, 18 with CKD not receiving dialysis and 16 with ESRD) received cinacalcet during the two studies. Study 1 included 36 subjects: 12 were healthy and 24 with CKD or ESRD were recruited into four groups of six subjects each, according to CLCR or ESRD receiving haemodialysis. Study 2 included ten subjects with ESRD receiving CAPD. The demographics and baseline characteristics of the subjects are summarised in table I: 67% (31/46) of the subjects were Clin Pharmacokinet 2005; 44 (5)

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male, 52% (24/46) were White, 41% (19/46) were Black and 7% (3/46) were Hispanic. Pharmacokinetics

The degree of renal impairment did not appear to affect the pharmacokinetics of cinacalcet, and no trend of increasing exposure (AUC and Cmax) occurred with decreasing renal function, haemodialysis or CAPD. Considerable overlap occurred in both AUC and Cmax between all groups (table II, figure 1 and figure 2). The moderate differences observed between groups in mean pharmacokinetic parameters are probably related to the high degree of variability between individuals, but no apparent change occurred in the shape of the plasma concentration-time curve with decreasing renal function or dialysis treatment (figure 3). In addition, there was no apparent consistent trend for increased variability with decreased renal function. No statistical outliers were observed in this study.

Pharmacokinetic parameters and protein binding of cinacalcet were similar between groups. Pharmacokinetic parameters were similar on dialysis and nondialysis days for haemodialysis subjects (table II). In addition, venous and arterial concentrations of cinacalcet measured over 7 hours during haemodialysis were virtually superimposable (figure 4). Exposure (AUC and Cmax) in CAPD subjects was comparable to that observed in haemodialysis subjects and other renal impairment groups (table II). Protein binding of cinacalcet was similar in all groups and ranged from 92.7% to 95.2% (table II), therefore the total drug concentration was reported. Parathyroid Hormone and Serum Calcium

In general, baseline PTH levels increased with worsening renal impairment (table III). The percentage decrease in PTH from baseline to nadir was generally consistent across all renal impairment groups, ranging from 64% to 83%. Nadir PTH concentrations occurred approximately 2–8 hours post-

100

Individual Mean

Cmax (ng/mL)

80

60

40

20

(n CA = PD 10 )

D ia ly si H (n s da D = y 6)

N

on

di a

ly si H (n s da D = y 6)

Se (n ve = re 6)

od (n era = te 6)

M

(n Mi = ld 6)

N (n orm = 12 al )

0

Renal function group Fig. 2. Observed maximum plasma concentration (Cmax) in subjects with normal renal function vs subjects with various degrees of renal impairment for 72 hours after administration of cinacalcet. CAPD = continuous ambulatory peritoneal dialysis; HD = haemodialysis.

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60

Normal (n = 12) Mild (n = 6) Moderate (n = 6) Severe (n = 6) ESRD (receiving HD) [n = 6]

50 40

sign, physical finding or other observation related to safety was considered clinically significant by the investigators. Discussion

30 20 10 0 0

20

40

60

80

Time (h) Fig. 3. Mean (SD) plasma concentrations of cinacalcet (ng/mL) over 72 hours after administration are shown for subjects with normal renal function; with mild, moderate or severe renal failure; and end-stage renal disease (ESRD; receiving haemodialysis [HD]).

dose, corresponding with cinacalcet tmax. These results are consistent with previous pharmacodynamics studies.[16] The percentage decrease in serum calcium from baseline to nadir and peak showed no consistent pattern related to renal function. Mean serum calcium baseline concentrations, percentage change from baseline, and time to nadir following cinacalcet administration lagged behind PTH and are presented in table III. Safety

No subject withdrew or discontinued prematurely due to an adverse event. Across both studies, eight subjects experienced adverse events of mild-tomoderate severity. The most common adverse events were gastrointestinal (diarrhoea, nausea and dyspepsia), and there was no apparent relation between adverse events and level of renal function. Some adverse events were considered by the investigators to be treatment related: in study 1, one healthy subject, one subject with mild CKD and one subject with moderate CKD experienced adverse events that were considered to be treatment related, and in study 2, three subjects experienced adverse events that were considered to be treatment related. However, no clinically significant trends were observed for any laboratory parameter and no vital © 2005 Adis Data Information BV. All rights reserved.

The results from these studies indicate that neither degree of renal impairment nor treatment with haemodialysis or CAPD alter the pharmacokinetics or pharmacodynamics of cinacalcet. Following a single 75mg dose, exposure to cinacalcet was comparable among all groups and no trend of increasing exposure was observed with decreasing renal function. This lack of effect of renal impairment on the pharmacokinetics of cinacalcet is consistent with the drug being highly metabolised, with little parent drug excreted in the urine. Pharmacokinetic parameters in subjects on haemodialysis were similar on dialysis and nondialysis days, and showed virtually identical arterial and venous concentrations of cinacalcet during dialysis. The lack of effect of both haemodialysis and CAPD on the pharmacokinetics of cinacalcet is not unexpected, since cinacalcet is a lipophilic drug that is approximately 96% protein bound, distributes extensively into tissue and is, therefore, not dialysable. Although renal impairment has been shown to occasionally affect the clearance of metabolised Plasma cinacalcet concentration (ng/mL)

Plasma cinacalcet concentration (ng/mL)

514

ESRD dialysis day venous (n = 6) ESRD dialysis day arterial (n = 6)

50 40 30 20 10 0 3

4

5

6

7

Time (h) Fig. 4. Arterial and venous plasma concentration-time profiles of cinacalcet in subjects receiving haemodialysis. Dialysis day mean (SD) cinacalcet concentration over time is shown for those receiving haemodialysis. ESRD = end-stage renal disease.

Clin Pharmacokinet 2005; 44 (5)

55.6 (4–120) Time to PTH nadir was 2–8 hours after dosing, with two exceptions (one subject at 72 hours and one at 48 hours).

17.0 (2–48)

CAPD = continuous ambulatory peritoneal dialysis; ESRD = end-stage renal disease; PTH = parathyroid hormone.

a

–8.8 (–17.9 to 2.5) –5.7 (–15.4 to 0)

22.3 (2–48) 12.7 (4–24)

–11.4 (–14.6 to –8.6) –4.4 (–7.5 to –1.1)

13.7 (8–24)

16.0 (12–24)

© 2005 Adis Data Information BV. All rights reserved.

Time of nadir [hours after dose]

Change at nadir (%)

–9.4 (–14.6 to –4.4)

–7.3 (–9.6 to –4.5)

–4.8 (–9.0 to 1.2)

2.59 (2.42–2.74) 2.20 (2.02–2.30) 2.25 (2.20–2.32) Baseline [mmol/L]

2.32 (2.10–2.42)

2.30 (2.20–2.47)

10.0 (4–12)

2.40 (1.97–2.72) 2.42 (2.27–2.59)

3.6 (2–8) 4.4 (2–8) 12.0 (2–48)a 4.7 (4–8) 4.3 (2–8) 17.0 (2–72)a

Serum calcium

33.1 (17–71)

515

3.0 (2–8) Time of nadir [hours after dose]

710.0 (188–2478)

–70.5 (–89 to –54) –63.6 (–85 to –46)

337.2 (150–633) 290.3 (107–727)

–76.5 (–95 to –60) –83.3 (–88 to –75)

179.7 (40–298) 72.2 (38–140)

–75.2 (–89 to –47) Change at nadir (%)

Baseline [ng/L]

Intact PTH

–56.6 (–80 to 0)

44.2 (19–109)

(CAPD; n = 10) nondialysis day (n = 6) dialysis day (n = 6)

–67.9 (–80 to –58)

ESRD ESRD (haemodialysis) severe (n = 6) moderate (n = 6) mild (n = 6) Renal function group

normal (n = 12) parameter

Pharmacodynamic

Table III. Parathyroid hormone (PTH) and calcium concentrations, mean change (range) and time of nadir

Pharmacokinetics of Cinacalcet

drugs,[17] this effect was not observed with cinacalcet. A high degree of interindividual variability in the pharmacokinetic parameters of cinacalcet was noted in this study, but was similar to that seen in other studies of cinacalcet involving healthy volunteers.[18,19] It is unlikely that the degree of variability was due to an inadequate sampling time because, for the majority of subjects, the amount of area extrapolated for the determination of AUC∞ was <20%. In addition, cinacalcet is metabolised by cytochrome P450 3A4;[20] therefore, effects of the high variability of this enzyme on the pharmacokinetics of cinacalcet must be considered. Single-dose administration of 75mg cinacalcet to study subjects was well tolerated across all degrees of renal function and no serious or severe adverse events were reported. No clinically significant changes occurred in laboratory tests, vital signs or ECGs over the course of the study. Thus, consistent with other studies of multiple dosing at 50 and 100mg,[3,4] cinacalcet was found to be well tolerated in study subjects. The results of this study demonstrate that the degree of renal impairment and mode of dialysis do not affect the pharmacokinetics or pharmacodynamics of cinacalcet. As the pharmacokinetics of cinacalcet are linear over the clinical dose range of 30–180mg and are not altered by multiple dosing,[16] the current results are applicable to the anticipated clinical dose range. Conclusion Since neither degree of renal impairment nor treatment with haemodialysis or CAPD affected the pharmacokinetics or pharmacodynamics of cinacalcet, modifications in the starting dose and titration of cinacalcet according to level of renal function or dialysis modality will not be necessary. Acknowledgements This work was funded by Amgen Inc., and all authors are employees of Amgen Inc. The authors would like to thank Thomas Marbury, Ramon Vargas and Marshall Sack for their contributions to this research. The manuscript is an accurate representation of the study results.

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References 1. Nemeth EF. Calcium receptors as novel drug targets. In: Bilezikian JP, Raisz LG, Rodan GA, editors. Principles in bone biology. San Diego (CA): San Diego Academic Press, 1996: 1019-35 2. Garrett JE, Capuano IV, Hammerland LG, et al. Molecular cloning and functional expression of human parathyroid calcium receptor cDNAs. J Biol Chem 1995; 270 (21): 12919-25 3. Quarles LD, Sherrard DJ, Adler S, et al. The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease. J Am Soc Nephrol 2003; 14 (3): 575-83 4. Lindberg JS, Moe SM, Goodman WG, et al. The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism. Kidney Int 2003; 63 (1): 248-54 5. Goodman WG, Hladik GA, Turner SA, et al. The calcimimetic agent AMG 073 lowers plasma parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism. J Am Soc Nephrol 2002; 13 (4): 1017-24 6. Block GA, Martin KJ, de Francisco AL, et al. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 2004; 350 (15): 1516-25 7. Voigts A, Felsenfeld AJ, Andress D, et al. Parathyroid hormone and bone histology: response to hypocalcemia in osteitis fibrosa. Kidney Int 1984; 25 (2): 445-52 8. Wang M, Hercz G, Sherrard DJ, et al. Relationship between intact 1-84 parathyroid hormone and bone histomorphometric parameters in dialysis patients without aluminum toxicity. Am J Kidney Dis 1995; 26 (5): 836-44 9. Block GA, Hulbert-Shearon TE, Levin NW, et al. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998; 31 (4): 607-17 10. Alem AM, Sherrard DJ, Gillen DL, et al. Increased risk of hip fracture among patients with end-stage renal disease. Kidney Int 2000; 58 (1): 396-9 11. Block GA, Port FK. Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients: recommendations for a change in management. Am J Kidney Dis 2000; 35 (6): 1226-37 12. Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who

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are undergoing dialysis. N Engl J Med 2000; 342 (20): 1478-83 13. Rix M, Andreassen H, Eskildsen P, et al. Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure. Kidney Int 1999; 56 (3): 1084-93 14. Vanholder R, De Smet R, Ringoir S. Factors influencing drug protein binding in patients with end stage renal failure. Eur J Clin Pharmacol 1993; 44 Suppl. 1: S17-21 15. Guidance for industry: pharmacokinetics in patients with impaired renal function: study design, data analysis, and impact on dosing and labelling. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, and Center for Biologics Evaluation and Research, 1998 May 16. Harris RZ, Padhi D, Marbury TC, et al. Pharmacokinetics, pharmacodynamics, and safety of cinacalcet HCI in hemodialysis patients at doses up to 200mg once daily. Am J Kidney Dis 2004; 44 (6): 1070-6 17. Ings RMJ. Pharmacokinetics and its application to drug development. In: Illing HPA, editor. Xenobiotic metabolism and disposition: the design of studies on novel compounds. Boca Raton (FL): CRC Press, 1989: 99-146 18. Padhi D, Harris R, Salfi M, et al. The pharmacokinetics of cinacalcet HCl are not altered by renal impairment or mode of renal replacement therapy [abstract]. World Congress of Nephrology Meeting; 2003 Jun 8-12; Berlin 19. Padhi D, Harris R, Salfi M, et al. Cinacalcet HCl absorption is not affected by coadministration of medications commonly prescribed to chronic kidney disease patients (pantoprazole sodium, sevelamer HCl, and calcium carbonate) [abstract]. American Society of Nephrology Meeting; 2003 Nov 12-17; San Diego 20. Sensipar® package insert. Thousand Oaks (CA): Amgen Inc., 2004

Correspondence and offprints: Dr Desmond Padhi, Department of Early Development, Mail Stop 38-3-A, Bldg 38, Room 3E-1-5, Amgen Inc., Thousand Oaks, CA 91360, USA. E-mail: [email protected]

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