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
2 Hoffmann-LaRoche, Grenzach-Wyhlen, Germany
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Abstract
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Background. 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 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 ng/ml; this decreased during first haemodialysis (after 4 h) to 4.9±0.9 ng/ml and after two subsequent haemodialysis treatments to 0.38±0.16 ng/ml. 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 ml/min. The total amount excreted at the first dialysis using the recovery rate measure was 364±98 µg and using the mean difference in inflow/outflow (arteriovenous) concentration (A-V difference method) it was 371±132 µg. About 36% of the total amount of ibandronate administered (1 mg) was removed by the first dialysis treatment.
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; osteoclast-mediated bone resorption; plasma concentration
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Introduction
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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-hydroxypropane-1,1-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 [35]. In a study with 2/3 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
1.000 ng/ml,
85% is protein bound. About 40% of ibandronate is bound in the bone. A dosage of 0.52 mg ibandronate once every 3 months is considered sufficient for osteoporosis therapy [7]. In healthy volunteers, the concentrationtime curve following intravenous administration declines in a multiexponential manner. The terminal half-life of 1016 h is estimated from urinary excretion rate and accounts for most of the given dose. The total body clearance is
130 ml/min. The mean volume of distribution is
150 l, indicating substantial distribution into extravascular tissues (bones). The renal clearance is
88 ml/min 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.
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Subjects and methods
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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 pg/nl), one patient had a mild hyperparathyroidism (65 pg/nl) 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
18 years; and provision of written informed consent. Exclusion criteria were: hypersensitivity to bisphosphonates; concomitant malignant disease, except paraneoplastic hypercalcaemic syndrome; platelets <120 000/µl; neutropenia <3000/µl; lymphopenia <1000/µl; haemorrhagic diathesis; haematocrit <26%; hypocalcaemia <2.03 mmol/l; 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
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Methods
After physical examination, safety laboratory variables were determined: aspartate transaminase (AST), alanine transaminase (ALT),
-glutamyltranspeptidase (
-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 pg/ml. 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 (501600 pg/ml). Calibration and calculation were performed using the quantification software of the Enzymune-Test®System 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:

| (|<|(|>|1|<|)|>|) |
The amount of excretion by the recovery rate method is:

| (|<|(|>|2|<|)|>|) |
The amount of excretion of ibandronate by the A-V difference method is:

| (|<|(|>|3|<|)|>|) |
The excretion rate from convection in the haemodialyser is defined as:

| (|<|(|>|4|<|)|>|) |
where Ae=amount excreted; Aecon=amount excreted from convection; ClIb=clearance of ibandronate; Cdo=mean dialysate concentration on outflow (ng/ml); Cpi=plasma concentration at midpoint of collecting period (1 h) (ng/ml); Cs=plasma concentration, including the addition i for inflow and o' for outflow; Qd=dialysate flow (ml/min); Qf=mean ultrafiltration rate; Qp=mean plasma flow on inflow; and t=total 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.
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Results
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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
. 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 ml/min, and 99.0±57.0 ml/min 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 364.4±98.2 µg. The total amount excreted, calculated by loss in plasma levels, was 371.2±131.6 µg. 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 ml/min over 4 h of the first dialysis session) was almost entirely due to diffusion.

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Fig. 2. Plasma ibandronate levels (ng/ml) on inflow (squares) and outflow (diamonds) over the 100 h following ibandronate administration.
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Fig. 3. Plasma ibandronate levels (ng/ml) on inflow (squares) and outflow (diamonds), and dialysate ibandronate levels (circles) over 4 h during the first dialysis session.
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Fig. 4. Outflow concentration of inflow ibandronate (%) over the 100 h following ibandronate administration. Results are represented as mean±SD.
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Fig. 5. Mean ibandronate clearance (±SD) (ml/min) at 14 h following ibandronate administration, during the first dialysis session, and at 4952 h, during the second dialysis session.
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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 pg/nl, respectively). There were also no significant changes in serum calcium levels from the beginning to the end of the study (Table 2
).
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Discussion
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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 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 13 months is sufficient for therapy in osteoporosis and metastatic bone disease. Normal doses of ibandronate administered every 13 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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Notes
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Correspondence and offprint requests to: Dr Raoul Bergner, Medizinische Klinik A, Klinikum der Stadt Ludwigshafen gGmbH, Bremserstrasse 79, D-67063 Ludwigshafen, Germany. Email: bergnerr{at}klilu.de 
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Received for publication: 11. 8.01
Accepted in revised form: 2. 2.02