Download Elimination of intravenously administered ibandronate in patients on

Nephrol Dial Transplant (2002) 17: 1281–1285
Original Article
Elimination of intravenously administered ibandronate in
patients on haemodialysis: a monocentre open study
Raoul Bergner1, Katja Dill1, Dietmar Boerner2 and Michael Uppenkamp1
1
Medizinische Klinik A, Klinikum der Stadt Ludwigshafen GmbH, Ludwigshafen, Germany and 2Hoffmann-LaRoche,
Grenzach-Wyhlen, Germany
Abstract
Background. Ibandronate is an inhibitor of osteoclastmediated bone resorption. This therapeutic effect is
utilized in the treatment of osteoporosis and metastatic
bone disease. The effect of ibandronate in patients on
haemodialysis with renal osteopathy has not been
studied since the pharmacokinetics of ibandronate
under haemodialysis are unknown.
Methods. We analysed the removal of ibandronate
from the plasma by haemodialysis in 12 chronic
haemodialysis patients suffering from end-stage renal
disease (ESRD). After intravenous administration of
1 mg ibandronate, the plasma concentration of ibandronate was determined in plasma samples drawn
before entering (inflow) and after passing through
(outflow) the haemodialyser, and in the dialysate at
1, 2, 3 and 4 h during the first haemodialysis session,
and after 1 and 4 h during the second and third dialysis
sessions.
Results. The back-extrapolated initial ibandronate
plasma level was 38.9"15.9 nguml; this decreased
during first haemodialysis (after 4 h) to 4.9"
0.9 nguml and after two subsequent haemodialysis
treatments to 0.38"0.16 nguml. Ibandronate concentration was reduced by 47% with every passage
through the dialyser. The total decrease of ibandronate
plasma concentration during the first 4 h of haemodialysis was 78% of plasma peak levels. The ibandronate dialysis plasma clearance was determined at
92"19 mlumin. The total amount excreted at the
first dialysis using the recovery rate measure was
364"98 mg and using the mean difference in
inflowuoutflow (arteriovenous) concentration (A-V
difference method) it was 371"132 mg. About 36%
of the total amount of ibandronate administered
(1 mg) was removed by the first dialysis treatment.
Correspondence and offprint requests to: Dr Raoul Bergner,
Medizinische Klinik A, Klinikum der Stadt Ludwigshafen gGmbH,
Bremserstrasse 79, D-67063 Ludwigshafen, Germany.
Email: [email protected]
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Conclusion. Ibandronate was efficiently removed by
haemodialysis. After three haemodialysis sessions the
ibandronate plasma levels were close to quantification
limit. One monthly dose of 1 mg ibandronate would
not result in elevated plasma levels in patients with
ESRD on haemodialysis treatment three times a week.
In haemodialysis patients, ibandronate should be
administered after the haemodialysis session.
Keywords: haemodialysis; ibandronate; osteoclastmediated bone resorption; plasma concentration
Introduction
Bisphosphonates, a class of drugs characterized by a
high affinity for mineralized tissues, are potent inhibitors of osteoclast-mediated bone resorption in vitro
and in vivo. Their mode of action is not completely
understood, but there is evidence that these compounds inhibit the activity of mature osteoclasts, and
presumably the proliferation, differentiation and
access to bone of their precursors [1,2]. Ibandronic
acid (3-(N-methyl-N-pentyl)amino-1-hydroxypropane1,1-di-phosphonic acid) is a new bisphosphonate that
prevents retinoid-induced hypercalcaemia in parathyroidectomized rats at considerably lower doses
than those of all previously known bisphosphonates.
A similar prevention of bone resorption is achieved
with ibandronate at 10-fold lower doses compared
with aminobutane bisphosphonate, and 2-fold lower
doses compared with risedronate, which so far has
been considered the most potent known bisphosphonate [3–5]. In a study with 2u3 nephrectomized
rats, ibandronate prevented the increase in bone
erosion and bone turnover [6]. Ibandronate monosodium salt monohydrate has a molecular weight of
359.24 Da and is detected in plasma as ibandronic
acid, with a molecular weight of 319.2 Da. At plasma
levels of O1.000 nguml, ;85% is protein bound.
About 40% of ibandronate is bound in the bone. A
2002 European Renal Association–European Dialysis and Transplant Association
1282
R. Bergner et al.
dosage of 0.5–2 mg ibandronate once every 3 months
is considered sufficient for osteoporosis therapy [7].
In healthy volunteers, the concentration–time curve
following intravenous administration declines in a
multiexponential manner. The terminal half-life of
10–16 h is estimated from urinary excretion rate and
accounts for most of the given dose. The total body
clearance is ;130 mlumin. The mean volume of
distribution is ;150 l, indicating substantial distribution into extravascular tissues (bones). The renal
clearance is ;88 mlumin in patients with normal
renal function [8]. To investigate the dialysability of
ibandronate in patients with end-stage renal disease
(ESRD) under dialysis treatment, we performed an
open study with 12 patients lacking any diuresis.
Subjects and methods
Patients
We investigated 12 patients (six females, six males) with
end-stage renal failure on dialysis treatment. All patients
lacked diuresis. Three patients suffered from adult polycystic kidney disease (APKD), two patients had diabetic
renal disease and two patients had nephroangiosclerosis.
One patient had reflux nephropathy, one suffered from
analgetica nephropathy, and a third patient had a haemolytic
uraemic syndrome. In two patients the cause of end-stage
renal faliure was unknown. None of the patients had been
nephrectomized. Five patients had a severe hyperparathyroidism ()200 pgunl), one patient had a mild hyperparathyroidism (65 pgunl) and six patients had normal values for
parathyroid hormone. Prior to participating in the study, all
subjects had to give their informed consent in accordance
with the Declaration of Helsinki. Inclusion criteria were:
patients with chronic renal failure on dialysis treatment; age
P18 years; and provision of written informed consent.
Exclusion criteria were: hypersensitivity to bisphosphonates;
concomitant malignant disease, except paraneoplastic hypercalcaemic syndrome; platelets -120 000uml; neutropenia
-3000uml; lymphopenia -1000uml; haemorrhagic diathesis;
haematocrit -26%; hypocalcaemia -2.03 mmolul; therapy
with bisphosphonates within the last 12 months preceeding
the first dose of study drug; aspirin-sensitive asthma in the
medical history; pre-treatment with aminoglycosides within
the last 4 weeks and during the trial; pregnancy; lactation;
serious liver disease; and administration of any investigational drug within the 30 days preceeding administration of
the study drug. Drugs other than aminoglycosides were
allowed, but had to be documented. Patients’ characteristics
are shown in Table 1.
Methods
After physical examination, safety laboratory variables were
determined: aspartate transaminase (AST), alanine transaminase (ALT), c-glutamyltranspeptidase (c-GT), platelets,
haematocrit, haemoglobin, erythrocytes, leukocytes, albumin, total protein and calcium (Table 2). Before the first
haemodialysis session (day 1), 1 mg ibandronate i.v. was
administered after insertion of dialysis needles. Blood samples
at inflow and outflow, and samples of dialysis fluid (10 ml) for
determination of ibandronate concentrations were collected
at 1, 2, 3 and 4 h after the drug was administered, at 1 and
4 h at second haemodialysis (day 3; 49 and 53 h in total), and
at 1 and 4 h at third haemodialysis (day 5; 97 and 100 h in
total) (Figure 1). The flow rates of blood and dialysis
fluid were documented at every haemodialysis session.
Before second haemodialysis the calcium blood levels were
checked. At the beginning of third haemodialysis the safety
laboratory values were determined again (Table 2).
The determination of ibandronate as free acid in the
plasma was performed by an enzyme linked immunosorbent
assay (ELISA). Owing to a plasma matrix effect, the calibration standards were prepared in the blank plasma of a
volunteer. The quantification limit was 50 pguml. The precision of the assay, as determined from the quality control
samples, was between 10.5 and 12.9%, and the inaccuracy
was between 5.7 and 14.1% within the calibration range
(50–1600 pguml). Calibration and calculation were performed using the quantification software of the EnzymuneTest1System ES600 (Boehringer Mannheim, Mannheim,
Germany), using the external standard method.
The duration of every dialysis was 4 h. The dialyser used
was an F8 (Fresenius Medical Care, Bad Homburg,
Germany) dialyser with a polysulfone membrane (1.8 m2).
The ultrafiltration rate was calculated based on the increase
in body weight since last dialysis.
Data analysis [9]
Ibandronate clearance by the recovery rate method is defined
as:
ClIb s(Qd qQf ) 3Cdo /Cpi (ml/min)
(1)
The amount of excretion by the recovery rate method is:
AeIb s(Qd qQf )3 Cdo 3 t/1000 (mg)
(2)
The amount of excretion of ibandronate by the A-V
difference method is:
AeIb sQp 3Csi (Qp Qf ) 3Cso 3 t/1000 (mg)
(3)
The excretion rate from convection in the haemodialyser is
defined as:
Aecon sCsi 3 0:143 Qf 3t/1000 (mg)
(4)
Table 1. Patient data
Males (ns6)
Body weight (kg)
Height (cm)
Age (years)
Body surface (m2)
Females (ns6)
Mean
Minimum
Maximum
SD
Mean
Minimum
Maximum
SD
69.9
173.7
57.5
1.829
44.6
160.0
38.0
1.436
96.0
192.0
74.0
2.157
17.3
11.0
12.4
0.3
68.8
161.8
63.2
1.729
49.6
151.0
54.0
1.435
93.8
178.0
71.0
2.119
14.7
8.9
5.8
0.2
Elimination of ibandronate in haemodialysis patients
1283
Fig. 1. Study design.
Table 2. Safety parameters in blood ("SD) before ibandronate
injection and at 96 h following administration
AST (Uul)
ALT (Uul)
c-GT (Uul)
Total protein (gudl)
Calcium (mmolul)
Albumin (gudl)
Haemoglobin (gudl)
Erythrocytes (106ml)
Leukocytes (1000uml)
Platelets (1000uml)
0h
96 h
7"3
8"4
16"11
6.8"0.6
2.36"0.17
3.9"0.5
10.8"1.7
3.5"0.4
6.0"1.5
194"63
7"3
8"4
17"11
7.0"0.8
2.48"0.33
4.1"0.5
10.7"1.2
3.6"0.6
6.2"2.1
209"60
where Aesamount excreted; Aeconsamount excreted from
convection; ClIbsclearance of ibandronate; Cdosmean
dialysate concentration on outflow (nguml); Cpisplasma
concentration at midpoint of collecting period (1 h) (nguml);
Cssplasma concentration, including the addition ‘i’ for
inflow and ‘o’ for outflow; Qdsdialysate flow (mlumin);
Qfsmean ultrafiltration rate; Qpsmean plasma flow on
inflow; and tstotal time of dialysis (min). The value at 0 h
was calculated as the intercept with the y-axis on a log-linear
regression.
We postulated that in the ultrafiltrate, the ibandronate
concentration is equal to non-protein bound ibandronate
concentration (;14%) at inflow, because the transmembrane pressure decreases constantly from inflow to
outflow. Therefore, most of the ultrafiltrate is produced
near inflow.
Results
All patients completed the study. No adverse effects
were noticed. The results of mean plasma levels at
inflow and outflow are shown in Figures 2 and 3.
Fig. 2. Plasma ibandronate levels (nguml) on inflow (squares)
and outflow (diamonds) over the 100 h following ibandronate
administration.
The results of ibandronate concentration in the
dialysate during first dialysis are shown in Figure 3.
The difference between inflow and outflow is relatively constant during all haemodialysis treatments (Figure 4). Dialysis eliminates about 47% of
the plasma ibandronate concentration. The higher
percentage at the end of the third dialysis is
because values were near the quantification limit. The
mean ibandronate clearance over 4 h of the first
haemodialysis session was 91.9"18.9 mlumin, and
99.0"57.0 mlumin over 4 h at the second haemodialysis session. At the third haemodialysis session the
ibandronate levels in dialysate were below the quantification limit, therefore it was impossible to calculate
ibandronate clearance (Figure 5). The total amount
excreted and found in dialysate at the first dialysis was
1284
Fig. 3. Plasma ibandronate levels (nguml) on inflow (squares) and
outflow (diamonds), and dialysate ibandronate levels (circles) over
4 h during the first dialysis session.
R. Bergner et al.
364.4"98.2 mg. The total amount excreted, calculated
by loss in plasma levels, was 371.2"131.6 mg. With
98.2% of ibandronate excreted, the recovery rate
method gave results almost equivalent to the A-V
difference method. The ibandronate excreted by
convection is ;2% of the total amount of ibandronate excreted. The total clearance of ibandronate
(91.9"18.9 mlumin over 4 h of the first dialysis
session) was almost entirely due to diffusion.
There was no significant difference in the decrease in
ibandronate level (from 4 to 49 h after ibandronate
application) between patients with high and normal
parathyroid hormone concentrations ()200 and
-55 pgunl, respectively). There were also no significant
changes in serum calcium levels from the beginning to
the end of the study (Table 2).
Discussion
Fig. 4. Outflow concentration of inflow ibandronate (%) over the
100 h following ibandronate administration. Results are represented
as mean"SD.
Fig. 5. Mean ibandronate clearance ("SD) (mlumin) at 1– 4 h
following ibandronate administration, during the first dialysis
session, and at 49–52 h, during the second dialysis session.
Ibandronate is an inhibitor of osteoclast-mediated
bone resorption. This therapeutic effect is utilized in
the treatment of osteoporosis and metastatic bone
disease. The effect of ibandronate in patients on
haemodialysis with renal osteopathy has not been
studied, since removal of ibandronate under haemodialysis is unknown. In experimental renal failure,
ibandronate prevents hyperparathyroid bone changes
and increases bone volume [6]. Clodronate given after
haemodialysis induces a significant decrease in serum
calcium levels and an increase of parathyroid hormone
in haemodialysis patients [10]. No abnormalities in the
serum calcium concentration were detected in our
patients during the study. Other electrolyte abnormalities, as have been reported in patients with
multiple myeloma after pamidronate administration,
were not measured [11].
Our study shows that ibandronate was removed
effectively by haemodialysis. The ibandronate clearance in dialysis is equal to the renal ibandronate
clearance in normal renal function [8]. The recovery
rate of 98% of ibandronate in the ultrafiltrate shows
that haemodialysis effectively removes ibandronate
before it binds to bone. The therapeutic application
of ibandronate should, however, be given after haemodialysis, since 36% of the total dose will be removed
when it is given immediately before haemodialysis.
The decrease in ibandronate levels between first and
second dialysis demonstrate ibandronate loss in bone
by irreversible binding. Between the second and third
haemodialysis sessions after ibandronate application,
this effect disappeared. After three 4-h haemodialysis
treatments, plasma ibandronate concentrations were
near the quantification limit.
The molecular weight of ibandronate (359.24 Da),
which is detected in plasma as ibandronic acid
(molecular weight 319.2 Da), suggests a good clearance, but the protein binding of ;86% suggests a low
dialysability. We therefore speculate that the protein
binding rapidly reaches a new equilibrium during the
Elimination of ibandronate in haemodialysis patients
flow through the dialyser. Ibandronate lost in the
plasma was almost completely found in the dialysate.
Thus, the two independent methods of calculation
elimination gave almost identical results. About 98%
of total ibandronate loss is caused by diffusion,
with 2% lost by convection; therefore, haemofiltration without any diffusion will not decrease
the ibandronate concentration effectively. We conclude that haemofiltration is not able to eliminate
ibandronate efficiently.
These data are nearly identical to those made with
clodronate [12,13]. In contrast to clodronate, ibandronate application every 1–3 months is sufficient for
therapy in osteoporosis and metastatic bone disease.
Normal doses of ibandronate administered every 1–3
months will be removed effectively by haemodialysis,
therefore no accumulation will occur in patients who
undergo haemodialysis three times weekly. Further
studies are needed to demonstrate the effects on renal
bone disease.
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Received for publication: 11.8.01
Accepted in revised form: 2.2.02