Nephrol Dial Transplant (2008) 23: 3720–3726
doi: 10.1093/ndt/gfn345
Advance Access publication 16 June 2008
Original Article
Pharmacodynamic effects of cinacalcet after kidney transplantation:
once- versus twice-daily dose
Nassim Kamar1,2 , Isabelle Gennero3,4 , Luciana Spataru1 , Laure Esposito1 , Joelle Guitard1 ,
Laurence Lavayssière1 , Olivier Cointault1 , Peggy Gandia5 , Dominique Durand1 and Lionel Rostaing1,4
1
Department of Nephrology, Dialysis and Multi-Organ Transplantation, CHU Toulouse-Rangueil, Toulouse University Hospital,
Toulouse, 2 INSERM U858, IFR 31, 1 av. Jean Poulhès, TSA 50032, 31059 Toulouse Cedex 9, 3 Laboratory of Biochemistry, CHU
Purpan, Toulouse University Hospital, Toulouse, 4 INSERM U563, IFR 30, 330 Ave. de Grande-Bretagne, TSA 40031,
31059 Toulouse Cedex 9 and 5 Laboratory of Pharmacology, CHU Purpan, Toulouse University Hosiptal, Toulouse, France
Abstract
Background. In the setting of kidney transplantation,
cinacalcet has been given, mainly, once daily, but also
twice daily. The aims of this prospective study were
to assess the acute pharmacodynamic effect of cinacalcet administrated once or twice daily to kidney transplant patients with normal renal function and persisting
hypercalcaemia due to hyperparathyroidism and to evaluate
1-year efficacy and tolerance of cinacalcet given at a dose of
30 mg b.i.d.
Methods. Eleven patients, who received a transplant 6
(6–59) months previously, were included in the study. A
first kinetic was done after administration of 60 mg of
cinacalcet at 8 a.m. After a washout period of 1 week,
the second kinetic was performed with cinacalcet given at
30 mg b.i.d within a 12-h period.
Results. During both kinetics, serum calcium (sCa), ionized calcium (sCa2+ ), albumin-corrected Ca and parathyroid hormone (PTH) levels decreased significantly. At 24 h
after the second kinetic, sCa2+ was significantly lower. After 1 year of cinacalcet treatment, given at the dose of 30 mg
b.i.d., there was a significant decrease in sCa, sCa2+ , PTH
levels and calcium × phosphorus (Ph) product. In contrast,
Ph levels increased significantly. There was no significant
change in renal function.
Conclusion. Once- or twice-daily acute administration of
cinacalcet to kidney-transplant patients has similar efficacy.
One-year administration of cinacalcet, given as two daily
doses, is safe and efficient.
Keywords: cinacalcet; daily dose; hyperparathyroidism;
renal function; renal transplantation
Correspondence and offprint requests to: Nassim Kamar, Department of
Nephrology, Dialysis and Multi-Organ Transplantation, Toulouse University Hospital, Toulouse, France. Tel: +33-5-6132-2684; Fax: +33-5-61322864; E-mail: kamar.n@chu-toulouse.fr
Introduction
Hyperparathyroidism is a common problem after successful kidney transplantation. At 1 year after transplantation, 10–20% of kidney transplant patients have developed
hyperparathyroidism despite normal renal function [1].
Lobo et al. previously found that only 23% of kidney
transplant patients with a serum creatinine level below
2 mg/dL had a normal serum parathyroid hormone (sPTH)
level [2]. Hyperparathyroidism alone, or via induced hypercalcaemia, is harmful to both bone metabolism [1,3]
and renal allograft function and histopathology [4]. Indeed,
studies have shown that systematic allograft biopsies performed at 6, 12 and 26 weeks after kidney transplantation
found nephrocalcinosis in 6, 12 and 17.6% of cases, respectively [5]. Nephrocalcinosis has been identified as a
strong predictive factor for chronic allograft nephropathy
[4]. Hence, persisting hypercalcaemia should be avoided
after kidney transplantation.
Cinacalcet, a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor and, consequently,
suppresses both serum calcium and parathyroid hormone
levels, has been successfully used in dialysis patients [6]
and in patients with primary hyperparathyroidism [7]. This
has prompted transplant physicians to treat kidney transplant patients with persisting hyperparathyroidism with
cinacalcet therapy [8–13]. In patients with primary hyperparathyroidism and normal renal function, cinacalcet has
been given twice daily [7]. In the setting of kidney transplantation, cinacalcet has been given, mainly, once daily
[8–10,12–16]. In only a few studies and case reports, it has
been used twice daily [15,17]. The aims of this prospective
study were to, first, compare the evolution of parathyroid
hormone, vitamin D, calcium and phosphorus concentrations after once- or twice-daily cinacalcet intakes in kidney
transplant patients with normal renal function, and second,
to evaluate 1-year efficacy and tolerance of cinacalcet given
at the dose of 30 mg b.i.d to kidney transplant patients with
persisting hypercalcaemia.
C The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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Cinacalcet after kidney transplantation
Patients and methods
Patients
Eleven consecutive kidney-transplant patients, with persisting hypercalcaemia (e.g., serum ionized calcium
>1.4 mmol/L) due to hyperparathyroidism at least 6 months
after transplantation, were included in this study after having given their informed consent. There were six men
and five women, ranging in age from 29 to 65 years
(mean 50.5). The median time since transplantation was
6 (6–59) months. Initial nephropathy was IgA nephropathy
(n = 2), interstitial nephropathy (n = 2), polycystic kidney
disease (n = 2), focal segmental glomerulosclerosis (n = 1),
lupus nephritis (n = 1) and undetermined nephropathy
(n = 3). All patients had been previously treated by
haemodialysis for 117.5 ± 33 months and had received a
kidney from a deceased donor. Four patients were receiving
a second transplant, whereas all others were receiving a first
transplant. The mean cold and warm ischaemia times were,
respectively, 21 (±8) h and 64 (±10) min. None of the patients experienced delayed graft function as defined by the
need for dialysis within the first week following transplantation. The time to reach a serum creatinine level below
220 µmol/L after transplantation was 7 ± 2 days. At inclusion, serum creatinine levels and calculated creatinine
clearance according to the Cockcroft–Gault formula were
119 ± 48 µmol/L and 56 ± 17 mL/min, respectively.
Three patients presented with acute rejection before starting the study. In all patients, immunosuppressive therapy
was based on calcineurin inhibitors [tacrolimus: (n = 8) or
cyclosporine A (n = 3)], with mycophenolic acid (n = 6),
sirolimus (n = 2) or everolimus (n = 2), with (n = 8) or
without (n = 3) steroids.
Methods
A first kinetic was done after administration of 60 mg
cinacalcet at 8 a.m. After a washout period of 1 week, the
second kinetic was performed with cinacalcet given at 30
mg b.i.d within a 12-h period. All patients were instructed
to fast overnight; only water was allowed until 1-h postdose. All patients took the same meals and at the same time
during both kinetics. For the second kinetic, blood sampling
started before the first 30 mg of cinacalcet were given.
At each kinetic, we measured different parameters.
Serum parathyroid hormone and cyclosporine A/tacrolimus
levels were measured before the cinacalcet intake and
at 1, 2, 3, 4, 6, 9, 12, 18 and 24 h later. Cyclosporine
A and tacrolimus 24-h area-under-the-curve (AUC0–24 h )
data were calculated using the trapezoidal rule. Serum
calcium (sCa), ionized calcium (sCa2+ ), phosphorus (sPh)
and albumin levels were measured before the cinacalcet
intake and at 2, 4, 6, 12 and 24 h later. At each time
point, albumin-corrected calcium was calculated using
the following formula: albumin-corrected calcium = sCa
(mmol/L) + 1-[albumin (g/L)/40]. 25-Hydroxy vitamin D3
(25(OH)D), 1,25-dihydroxy vitamin D3 [1,25-(OH)2 -vit
D3 ], and fibroblast growth factor 23 (FGF-23) were
also measured before the cinacalcet intake and at 6, 12
and 24 h later. After the second kinetic, patients were
given cinacalcet at 30 mg b.i.d. Thereafter, the following
3721
parameters were assessed at 1, 3, 6, 9 and 12 months after
starting cinacalcet therapy: sCa, sCa2+ , sPh, sPTH, serum
creatinine and cyclosporine/tacrolimus levels, as well
as urine calcium/creatinine levels. Blood samples were
always obtained 12 h after the last intake of cinacalcet.
Measurement of sPTH. Serum intact PTH (i-PTH,
R
R
Cobas
) was measured by an Elecsys
automated analyser
using a two-site chemiluminescent enzyme immunometric
assay (Roche Diagnostics, Mannheim, Germany).
Measurement of vitamin D. For 1,25-dihydroxy vitamin D
(1,25-(OH)2 -vit D) analysis, patient samples were first
delipidated. Then, 1,25-(OH)2 -vit D was extracted from potential cross-reactants by immunoextraction with a highly
specific solid phase monoclonal anti-1,25-(OH)2 -vit D and
followed by quantitation by 125 I radioimmunoassay (Immunodiagnostic Systems Limited (IDS Ltd), Bolton, UK).
Measurement of FGF-23. The human FGF-23 (C-Term)
kit (Immunotopics, Inc. San Clemente, CA, USA) was used
to assay sera for FGF-23 according to the manufacturer’s
instructions. It is a commercially available two-site enzymelinked immunosorbent assay (ELISA) kit that detects epitopes within the carboxyl-terminal portion of FGF-23.
Measurement of cyclosporine A and tacrolimus. For the
measurement of cyclosporine A and tacrolimus levels,
both cyclosporine A and tacrolimus were determined using
R
R
the Flex
-Dimension
validated automated immunoassay
(Newark, NJ, USA).
Statistical analyses
Reported values represent either means ± SE or medians (ranges). Proportions were compared by the χ2 -test or
Fisher’s exact test. Quantitative variables were compared
by the non-parametric Mann–Whitney test. During each kinetic and treatment follow-up, quantitative variables were
compared by the non-parametric Friedman test for serial
measurements and the Wilcoxon test. A P-value <0.05 was
considered to be statistically significant.
Results
Patient characteristics
Before transplantation, 10 out of the 11 patients were treated
for hyperparathyroidism. Three had a parathyroid adenoma.
Calcium phosphorus and parathyroid status before and at
inclusion are summarized in Table 1.
Acute effect of once- or twice-daily dose of cinacalcet
on serum parathyroid hormone
Serum parathyroid hormone levels decreased significantly
during both kinetics (P < 0.0001; Figure 1A). After administration of cinacalcet, sPTH decreased to a nadir that
occurred 2 h after dosing. At nadir, sPTH levels had
decreased respectively by 76% (P < 0.0001) and 70%
(P < 0.0001), as compared to pre-kinetic levels after
3722
N. Kamar et al.
Table 1. Patient characteristics
Before transplantation
History of parathyroid adenoma
Hyperparathyroidism therapy
cinacalcet + sevelamer
calcium + vitamin D analogue
cinacalcet
calcium + sevelamer + vitamin D analogue
sevelamer
At transplantation (Day 0)
sPTH level (pg/mL) (n = 15–85)
sCa level (mmol/L) (n = 2.2–2.6)
sPh level (mmol/L) (n = 0.8–1.5)
AP (U/L) (n = 100–280)
One-month posttransplantation
Serum creatinine level (µmol/L)
Creatinine clearance (mL/min)
sPTH level (pg/mL) (n = 15–85)
sCa level (mmol/L) (n = 2.2–2.6)
sCa2+ (mmol/L) (n = 1.16–1.29)
sPh level (mmol/L) (n = 0.8–1.5)
AP (U/L) (n = 100–280)
Three-month posttransplantation
Serum creatinine level (µmol/L)
Creatinine clearance (mL/min)
sPTH level (pg/mL) (n = 15–85)
sCa level (mmol/L) (n = 2.2–2.6)
sCa2+ (mmol/L) (n = 1.16–1.29)
sPh level (mmol/L) (n = 0.8–1.5)
AP (U/L) (n = 100–280)
Serum creatinine level at first kinetic (µmol/L)
Creatinine clearance at first kinetic (mL/min)
Serum creatinine level at second kinetic (µmol/L)
Creatinine clearance at second kinetic (mL/min)
3/11
4
3
1
1
1
407 (295–922)
2.46 (2.11–2.71)
1.64 (1.16–1.98)
157 (69–602)
123 ± 8
54 ± 5
223 (88–606)
2.71 (2.35–2.79)
1.51 (1.37–1.56)
0.49 (0.4–0.82)
181 (69–1133)
126 ± 9
54 ± 6
326 (80–655)
2.64 (2.3–2.97)
1.51 (1.37–1.56)
0.68 (0.37–0.96)
285 (102–678)
119 ± 9
56 ± 5
118 ± 8
56 ± 4
sPTH, serum parathyroid hormone; sCa, serum calcium; sCa2+ , serum
ionized calcium; sPh, serum phosphorus; AP, alkaline phosphatase.
administration of 60 and 30 mg of cinacalcet. When given
once daily, cinacalcet induced a decrease in sPTH levels for
9 h, followed by an increase until the next dose intake. Consequently, no significant difference was observed in sPTH
levels between T0 and T24 (i.e., 319 ± 88 versus 303 ± 118
pg/mL; P = 0.09). In contrast, cinacalcet given twice daily
induced a significant decrease in sPTH level, i.e., 295 ± 75
at T0 versus 217 ± 68 pg/mL (P = 0.0009). No significant
difference was observed in sPTH levels at any time point
between both kinetic profiles.
Acute effect of the once- or twice-daily cinacalcet intake
on calcium–phosphorus parameters
Serum calcium, serum ionized calcium and albumincorrected calcium levels decreased significantly during
both kinetic profiles (Figure 1B–D). After a once-daily dose
of cinacalcet, sCa, sCa2+ and albumin-corrected Ca levels
decreased significantly from, respectively, 2.7 (± 0.04) to
2.58 (±0.06) mmol/L (P = 0.02), from 1.52 (±0.02) to
1.43 (±0.03) mmol/L (P = 0.0009) and from 2.68 (±0.05)
to 2.6 (±0.04) mmol/L at (P = 0.02) at T0 to T24. After the
twice-daily dose of cinacalcet, sCa, sCa2+ and albumincorrected Ca levels also decreased significantly, respectively, from 2.65 (±0.04) to 2.53 (±0.04) mmol/L (P =
0.005), from 1.5 (±0.03) to 1.38 (±0.03) mmol/L (P =
0.003) and from 2.66 (±0.04) to 2.57 (±0.03) mmol/L
(P = 0.02) between T0 and T24. No significant difference
was observed in sCa and albumin-corrected Ca levels at any
time point between both kinetic profiles. At T24, sCa and
albumin-corrected calcium levels were lower after twicethan once-daily cinacalcet dose intakes, but the difference
was not statistically significant. In contrast, at T24, the
sCa2+ level was significantly lower when cinacalcet was
administrated twice daily (P = 0.02).
Serum phosphorus levels remained unchanged after the
cinacalcet intake, i.e., 0.71 ± 0.05 at T0 versus 0.68 ±
0.07 mmol/L after a once-daily dose and 0.73 ± 0.06 at T0
versus 0.78 ± 0.08 mmol/L after a twice-daily dose (Figure
1E). No significant difference was observed in sPh levels at
any time point between both kinetic profiles. At T24, sPh
was higher when cinacalcet was given at the twice-daily
dose, but the difference was not statistically different.
Calcium–phosphorus product did not change significantly after giving cinacalcet at the once-daily dose, i.e.,
1.93 ± 0.13 mmol2 /L2 at T0 versus 1.76 ± 0.18 at T24
(ns). In contrast, when cinacalcet was given at the twicedaily dose it decreased significantly from 1.96 ± 0.17 to
1.57 ± 0.2 mmol2 /L2 (P = 0.05; Figure 1F). No significant difference was observed in the calcium–phosphorus
product at any time point between both the kinetic profiles.
Acute effect of once- or twice-daily dose of cinacalcet
on vitamin D and FGF-23 levels
Before the cinacalcet intake, 25-(OH)-vit D3 and 1,25(OH)2 -vit D3 levels were within the normal ranges in all
patients. 25-(OH)-vit D3 levels did not change significantly
within the 24-h study period, i.e., 15.9 ± 1.34 at T0 versus 15.7 ± 1.8 ng/mL at T24 after the once-daily dose and
16.1 ± 1.55 at T0 versus 16.1 ± 2.3 ng/mL at T24 after the
twice-daily dose.
Overall, there was a trend towards a decrease in 1,25(OH)2 -vit D3 levels, but this was not statistically significant.
However, when comparing 1,25-(OH)2 -vit D3 levels at T0
and T24, it decreased from 33.9 ± 5.4 at T0 to 25.4 ±
3.6 pg/mL at T24 (P = 0.02) after the once-daily dose and
from 34.2 ± 3.6 at T0 to 26 ± 3.4 pg/mL at T24 (P = 0.05)
after the twice-daily dose.
Finally, serum FGF-23 levels decreased slightly during
the study period, from 145 ± 57 at T0 to 102 ± 32 IU/mL at
T24 (P = 0.2) after the once-daily dose and from 163 ± 61
at T0 to 116 ± 59 IU/mL (P = 0.08) after the twice-daily
dose. No significant difference was observed in 25-(OH)vit D3 , 1,25-(OH)2 -vit D3 , and serum FGF-23 levels at any
time point between both kinetic profiles.
Acute effect of once- or twice-daily dose of cinacalcet
on tacrolimus and cyclosporine levels
Tacrolimus AUC0–24 h did not differ significantly when
cinacalcet was given once (241 ± 35 ng h/mL) or twice
daily (211 ± 27 ng h/mL). Cyclosporine A AUC0–24 h was,
respectively, 4944 ± 654 ng h/mL after cinacalcet was administrated at the once-daily dose and was 4280 ± 163 ng
h/mL after the twice-daily dose. Cyclosporine A AUCs0–24 h
was not statistically compared because of the small number
of patients receiving this in our study (n = 3).
3723
300
P<0.0001
sPTH level (pg/mL)
250
200
150
100
50
0
P<0.0001
A
T0
T1
T2
T3
T4
T6
T9
T21
T81 T42
Albumin- corrected Ca level (mmol/L)
Cinacalcet after kidney transplantation
2.8
P=0.003
2.7
2.6
2.5
P=0.03
D
2.4
T0
T2
T4
T6
T12
T24
1
P<0.0001
2.6
2.5
2.4
P=0.002
B
T0
T2
T4
T6
T12
0.8
0.6
0.4
ns
E
0.2
T24
T0
1.6
T2
T4
T6
T12
T24
2.5
*
P<0.0001
1.5
**
*
1.4
P<0.0001
C
1.3
T0
T2
T4
T6
T12
**
T24
Serum Ca x Ph (mmol²/L²)
sCa²+ level (mmol/L)
ns
2.7
sPh level (mmol/L)
sCa level (mmol/L)
2.8
P=0.05
2
1.5
F
ns
1
T0
T2
T4
T6
T12
T24
Fig. 1. Outcome of serum parathyroid hormone, serum calcium, serum ionized calcium, albumin-corrected calcium, phosphorus and calcium–
phosphorus product after cinacalcet administrated at once (- - - 䉱- - - )- or twice (–䊏–)-daily dose. P-values correspond to overall changes of each
parameter (Friedman test for repeated measurements).
One-year effect of cinacalcet given at the twice-daily dose
After both kinetic profiles, all 11 patients received cinacalcet at the dose of 30 mg b.i.d. None of the patients received
any vitamin D analogue or phosphorus binder. Two months
after having started the study, one patient presented with
a BK virus nephropathy, which led to graft loss 6 months
later. Hence, the results of the ten remaining patients are
presented below.
Effect of 1-year therapy of cinacalcet, given at the
twice-daily dose, on serum parathyroid levels and calcium
phosphorus parameters (Figure 2A–C)
After 1 year of cinacalcet therapy given at 30 mg b.i.d, sPTH
decreased significantly from 319 ± 88 to 148 ± 25 µmol/L
(P = 0.04). Serum calcium and serum ionized calcium levels also decreased significantly from 2.7 ±0.04 to 2.42 ±
0.05 mmol/L (P = 0.01) and from 1.52 ± 0.02 to 1.34 ±
0.02 mmol/L (P = 0.008), respectively. Albumin-corrected
calcium levels decreased from 2.68 ± 0.05 to 2.49 ± 0.07
(P = 0.06). Conversely, serum phosphorus levels significantly increased from 0.68 ± 0.07 to 1.01 ± 0.1 mmol/L
(P = 0.04). The calcium–phosphorus product decreased
significantly from 1.93 ± 0.13 to 1.35 ± 0.14 mmol2 /L2
(P = 0.008). Alkaline phosphate decreased significantly
from 339 ± 34 to 144 ± 36 IU/L (P = 0.046).
Effect of 1-year therapy of cinacalcet, given at the
twice-daily dose, on renal parameters (Figure 2D)
With respect (Figure 2D) to renal function, no significant
change in either serum creatinine level or in calculated creatinine clearance was observed (119 ± 9 versus 118 ±
8 µmol/L, and 56 ± 5 versus 59 ± 7 ml/min, respectively).
No significant change was observed in 24-h calciuria or
in urine calcium/creatinine, respectively [119.5 (37–237)
N. Kamar et al.
P=0.04
300
250
200
150
100
50
A
0
Baseline
M1
M3
M9
M6
M12
Serum calcium: P = 0.01
Albumin-corrected calcium: P = 0.06
… … Serum ionized calcium P = 0.0008
2.8
2.6
1.4
2.4
1.2
2.2
B
1
2
Baseline
Ca x Ph product
… … Serum phosphorus
2
P=0.008
1.5
1
0.5
0
P=0.04
C
M1
M3
M6
M9
M12
Serum creatinine
… … Creatinine clearance
140
Serum cretainine (µmol/L)
Serum phosphorus (mmol/L) and
Ca X Ph product (mmol²/L²)
3
2.5
70
ns
60
130
120
50
ns
110
M1
M3
M6
M9
M12
40
D
100
Baseline
1.6
Serum ionized calcium
Serum PTH level (pg/mL)
350
Baseline
M1
M3
M6
M9
Creatinine clearance (mL/min)
Serum calcium & albumin-corrected calcium
3724
30
M12
Fig. 2. Outcome of serum parathyroid hormone, serum calcium, serum ionized calcium, albumin-corrected calcium, phosphorus, calcium–phosphorus
product and renal function after 1 year of cinacalcet therapy given at twice-daily doses. P-values correspond to overall changes of each parameter
(Friedman test for repeated measurements). ∗ P = 0.05; ∗∗ P = 0.02. Abbreviation: Ca × Ph, calcium–phosphorus.
at baseline versus 114 (70–270) mg/day 12 months later
and 0.19 (0.08–0.27) at baseline versus 0.16 (0.13–0.30)].
Systolic and diastolic blood pressure, as well as the number and dosage of antihypertensive therapy remained unchanged (data not shown).
Safety profile
None of the patients presented with acute rejection, experienced any gastrointestinal side effects or developed
hypocalcaemia.
Discussion
Because of its harmful affect upon renal function and histology [4,5], as well as upon bone metabolism [3], hypercalcaemia should be avoided after kidney transplantation. For
this reason, and in order to treat persisting hyperparathyroidism, subtotal parathyroidectomy has been previously
the only option. However, this has been reported to be
responsible, in many cases, for significant worsening of
renal allograft function [18,19]. The efficacy and safety
of using cinacalcet in dialysis patients with secondary hyperparathyroidism has prompted transplant physicians to
use it in kidney transplant patients with persisting hyperparathyroidism. In this setting, the use of cinacalcet has
not yet been approved and many questions remain unanswered, i.e., when should cinacalcet therapy be started and
at what dosage should cinacalcet be given? Indeed, in patients with end-stage renal disease, cinacalcet is given at a
once-daily dose [6]. Conversely, in patients with primary
hyperparathyroidism and normal renal function, Peacock
et al. administrated cinacalcet twice daily [7]. Finally, in
kidney transplant patients who have nearly normal renal
function, cinacalcet has been given both once [8–10,12–
15] and twice daily [15]. Hence, in this prospective study,
we assessed the acute pharmacodynamic effect of cinacalcet when given once or twice daily and evaluated the efficacy and tolerance of cinacalcet given twice daily in the
setting of kidney transplantation. We found that the acute
pharmacodynamic effect of cinacalcet was quite similar
when given once or twice daily and that 1-year therapy of
cinacalcet given at the dose of 30 mg b.i.d was efficient and
safe.
Cinacalcet is cleared predominantly by oxidative hepatic metabolism and minimally by renal mechanisms.
Renal impairment can cause changes in absorption,
hepatic metabolism and plasma protein binding and distribution that could potentially impact on its pharmacokinetic and pharmacodynamic characteristics [20]. Previously, Padhi et al. assessed the effect of renal function
and dialysis on the pharmacokinetics and pharmacodynamics of cinacalcet [21]. Following a single-dose (75 mg)
administration of cinacalcet, the authors concluded that
the increasing degree of renal impairment did not significantly modify either its pharmacokinetic profile, i.e., the
area under the curve and maximal concentration, or its
Cinacalcet after kidney transplantation
3725
pharmacodynamic effects. However, the percentage of decrease in sPTH concentrations from baseline to nadir was
56.6% in patients with normal renal function versus 67.9,
75.2 and 83.3% in patients with mild, moderate and severe
renal function, respectively [21]. At steady state, Harris
et al. showed that, in haemodialysis patients receiving
150 mg of cinacalcet once daily, nadir sPTH levels occurred
at ∼2 to 3 h after dosing, which corresponded with the
maximal concentration of cinacalcet [22]. However, sPTH
levels returned to nearly pre-dose levels at 8 h after dosing
[22]. A similar finding was observed in patients with normal renal function treated by cinacalcet for primary hyperparathyroidism [7]. Very recently, Serra et al. compared the
pharmacokinetic and pharmacodynamic effects of cinacalcet given at 30 mg and then 60 mg once daily in stable
kidney transplantation. They found an inverse correlation
between cinacalcet and parathyroid hormone levels. The
nadir of PTH level occurred 3 h after cinacalcet dosing.
At nadir, cinacalcet given at 30 and 60 mg lowered sPTH
levels by 60 and 68% [23]. In the present study, after dosing
cinacalcet at 60 mg once daily, sPTH decreased by 76% at
2 h and increased thereafter. Twenty-four hours after the
cinacalcet intake at 60 mg once daily, sPTH level was 23%
lower than at pre-dose. During the second kinetic, after
dosing cinacalcet at 30 mg, sPTH level decreased by 70%
at 2 h and increased thereafter. However, because of the
second administration of 30 mg of cinacalcet at 12 h later,
sPTH level decreased further, resulting in an overall decrease of 44% compared to pre-dose levels. Serum calcium,
ionized calcium and albumin-corrected calcium concentrations decreased significantly independently of the number
of cinacalcet intakes. However, when cinacalcet was given
once daily, serum calcium, ionized calcium and albumincorrected calcium decreased until T12 and increased thereafter. In contrast, when cinacalcet was given twice daily, calcium parameters did not increase after T12, but decreased
furthermore. This is probably related to the additional decrease of sPTH due to the second dose of cinacalcet. At
T24, serum ionized calcium level was significantly lower
when cinacalcet was given twice than once daily. In studies
by Harris et al. [22], Peacock et al. [7] and Serra et al.
[23], serum calcium concentrations remained relatively
constant during the 24-h dosing interval. With respect to
phosphorus levels, it increased when cinacalcet was given
once or twice daily. However, the increase was higher when
cinacalcet was given twice daily.
Finally, in the present study, serum phosphorus, 25-(OH)vit D3 , and serum FGF-23 levels, as well as the calcium–
phosphorus product remained constant during the 24-h dosing interval. Compared to baseline, only 1,25-(OH)2 -vit
D3 decreased significantly, independently of the number
of cinacalcet doses. Hence, in summary, even though sPTH
decreased somewhat more when cinacalcet was given twice
daily, the administration of cinacalcet once or twice daily
was quite similar. In addition, given the known beneficial effects of sPTH for normal bone formation, the normalization of PTH does not seem to be a valid objective.
Conversely, the variations of sPTH levels in patients receiving cinacalcet may lead to improved bone mineralization. Indeed, in an animal model, daily intermittent, but not
sustained, decreases in PTH levels by a calcimimetic compound have an ‘anabolic-like’ effect on bones with a chronic
renal insufficiency-related low-turnover lesion [24]. In dialysis patients, suppression of sPTH with cinacalcet reverses
bone loss in the proximal femur, but does not affect bone
mineral density of the lumbar spine [25]. The authors speculate that cinacalcet may have a different effect on trabecular
and cortical bone [25].
Similar to previous published reports, 1-year cinacalcet
therapy given twice daily was associated with a significant
decrease in serum calcium levels [8–10,12,13,15,16]. Conflicting data regarding the effect of cinacalcet upon serum
parathyroid, phosphorus level, renal function, and urine calcium excretion have been published (Table 2). In the present
study, there was a significant decrease in the sPTH level and
a significant increase in the serum phosphorus level without
any renal side effects.
Subtotal parathyroidectomy has been incriminated by
some authors to result in a significant worsening of renal
allograft function [18,19] that does not however seem to be
harmful on graft survival [26]. The mechanism of deterioration of renal function remains unknown. Several authors
speculate that it is related to a haemodynamic mechanism
[19] as sPTH has a vasodilatory effect on pre-glomerular
vessels [27]. Similarly, after cinacalcet therapy, some authors have reported a decrease in renal function [8,15]. This
was not observed in the present study. Finally, conversely
to previous case reports that showed that high doses of
cinacalcet induce hypercalciuria [17,28], we did not observe any increase in urine calcium excretion after 1 year of
cinacalcet treatment. Despite the higher doses of cinacalcet used in our study, none of the patients presented with
Table 2. Review of published reports on the use of cinacalcet after kidney transplantation
Studies
Number
Follow-up (months)
Maximal daily dose
sPTH level
sCa
sPh
Renal function
Calciuria
Serra et al. [9]
Kruse et al. [8]
Srinivas et al. [10]
Leca et al. [12]
Szwarc et al. [13]
El-Amm et al. [15]
Bergua et al. [16]
Present study
11
14
11
10
9
18
13
10
2.5
3
6
6
6
6
6
12
60 mg
30 mg
30 mg
60 mg
30 mg
180 mga
60 mg
60 mga
↓ (23%)
→
→
↓ (54%)
↓ (13.5%)
↓ (42%)
↓ (13%)
↓ (54%)
↓
↓
↓
↓
↓
↓
↓
↓
↑
→
↑
→
→
↑
↑
↑
→
↓
→
→
→
↓
→
→
→
ND
ND
ND
→
ND
→
→
sPTH, serum parathyroid hormone; sCa, serum calcium; sPh, serum phosphorus; ND, not determined.
a Cinacalcet given twice daily.
3726
N. Kamar et al.
hypocalcaemia or complained of gastrointestinal disorders.
Finally, recently Falck et al. have reported that cinacalcet
induces a significant decrease in tacrolimus, but not in cyclosporine A [29]. In the present study, we did not find a
difference in tacrolimus area under the curve in patients receiving cinacalcet once or twice daily. However, we did not
compare the tacrolimus area-under-the-curve before and
after cinacalcet therapy.
The main limitations of our studies were the small number of patients enrolled and the lack of dosage of cinacalcet
during both kinetics. In addition, we do not know whether
the similar efficacy observed after once or twice-daily dose
of acute administration of cinacalcet will remain unchanged
after once or twice-daily dose of chronic administration.
Indeed, we did not compare the long-term effect of once
or twice-daily chronic administration of cinacalcet. Further studies are required to respond to this issue. A reduced
compliance may be higher when cinacalcet is administrated
twice daily and this possible reduced compliance should
be considered when evaluating both strategies. Finally, the
acute pharmacodynamic effect of cinacalcet observed in
our patients who had a mild to moderate persistent hyperparathyroidism, may be different in those who have severe
hypoparathyroidism.
In conclusion, once or twice-daily acute administration of
cinacalcet to kidney-transplant patients with persisting HPT
has similar efficacy. One-year administration of cinacalcet,
given as two daily doses, is safe and efficient.
Acknowledgement.
We thank Dr D. Attaf (Paris) for supporting this study.
Conflict of interest statement. None declared.
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Received for publication: 6.4.08
Accepted in revised form: 26.5.08