BACKGROUND: Cases of impaired renal function have been reported in patients who had been treated with both zoledronic acid and thalidomide for myeloma. Hence, we conducted a safety study of zoledronic acid and thalidomide in myeloma patients participating in a trial of maintenance therapy. METHODS: Twenty-four patients who were enrolled in a large randomized trial of thalidomide vs no thalidomide maintenance therapy for myeloma, in which all patients also received zoledronic acid, were recruited to a pharmacokinetic and renal safety sub-study, and followed for up to 16 months. RESULTS: No significant differences by Wilcoxon rank-sum statistic were found in zoledronic acid pharmacokinetics or renal safety for up to 16 months in patients randomized to thalidomide or not. CONCLUSION: In myeloma patients receiving maintenance therapy, the combination of zoledronic acid and thalidomide appears to confer no additional renal safety risks over zoledronic acid alone

Andrew Roberts

Andrew Spencer

Christina Ravera

F Legay

Horst Schran

JR Berenson

Kevin Lynch

Michael Copeman

Nola Kennedy

Sanela Bilic

Serge Cremers

SG Jones

T Chen

Terry Neeman

BMC Clinical Pharmacology

English

PubMed

Springer - Publisher Connector

Renal safety of zoledronic acid with thalidomide in patients with myeloma: a pharmacokinetic and safety sub-study

BioMed CentralBMC Clinical Pharmacology
ssOpen AcceResearch article
Renal safety of zoledronic acid with thalidomide in patients with 
myeloma: a pharmacokinetic and safety sub-study
Andrew Spencer*1, Andrew Roberts2, Nola Kennedy1, Christina Ravera3, 
Serge Cremers3, Sanela Bilic3, Terry Neeman4, Michael Copeman5, 
Horst Schran3 and Kevin Lynch5
Address: 1Department of Haematology and Bone Marrow Transplantation, The Alfred Hospital, Prahan, Victoria, Australia, 2Department of 
Haematology, Royal Melbourne Hospital, Parkville, Victoria, Australia, 3Department of Clinical Pharmacology, Novartis Pharmaceuticals 
Corporation, East Hanover, New Jersey 07936, USA, 4Covance Pty. Ltd., Canberra, ACT, Australia and 5Novartis Pharmaceuticals Australia Pty. 
Ltd., 54 Waterloo Rd, North Ryde NSW 2113, Australia
Email: Andrew Spencer* - aspencer@netspace.net.au; Andrew Roberts - aroberts@unimelb.edu.au; Nola Kennedy - n.kennedy@alfred.org.au; 
Christina Ravera - Christina.ravera@novartis.com; Serge Cremers - mcopeman@bigpond.net.au; Sanela Bilic - sanela.bilic@novartis.com; 
Terry Neeman - terry.neeman@covance.com; Michael Copeman - mcopeman@bigpond.net.au; Horst Schran - horst.schran@novartis.com; 
Kevin Lynch - kevin-1.lynch@novartis.com
* Corresponding author    
Abstract
Background: Cases of impaired renal function have been reported in patients who had been
treated with both zoledronic acid and thalidomide for myeloma. Hence, we conducted a safety
study of zoledronic acid and thalidomide in myeloma patients participating in a trial of maintenance
therapy.
Methods: Twenty-four patients who were enrolled in a large randomized trial of thalidomide vs
no thalidomide maintenance therapy for myeloma, in which all patients also received zoledronic
acid, were recruited to a pharmacokinetic and renal safety sub-study, and followed for up to 16
months.
Results: No significant differences by Wilcoxon rank-sum statistic were found in zoledronic acid
pharmacokinetics or renal safety for up to 16 months in patients randomized to thalidomide or not.
Conclusion: In myeloma patients receiving maintenance therapy, the combination of zoledronic
acid and thalidomide appears to confer no additional renal safety risks over zoledronic acid alone.
Background
Modern therapy of multiple myeloma (MM) combines
treatments to induce disease response (e.g. thalidomide,
corticosteroids and cytotoxic agents) with supportive care
to prevent bone and infective complications (e.g. bisphos-
phonates and antibiotics). However, combining agents
might cause interactions that increase toxicity or lessen
efficacy. Case reports suggested that MM patients receiving
zoledronic acid combined with thalidomide had higher
risks of renal impairment [1]. Hence, the United States'
Food and Drug Administration requested that Novartis
(manufacturer of zoledronic acid) conduct a study to look
for pharmacokinetic interaction between zoledronic acid
Published: 31 March 2008
BMC Clinical Pharmacology 2008, 8:2 doi:10.1186/1472-6904-8-2
Received: 7 June 2007
Accepted: 31 March 2008
This article is available from: http://www.biomedcentral.com/1472-6904/8/2
© 2008 Spencer et al; licensee BioMed Central Ltd. 
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), 
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 4
(page number not for citation purposes)
BMC Clinical Pharmacology 2008, 8:2 http://www.biomedcentral.com/1472-6904/8/2and thalidomide, and to monitor renal safety of MM
patients receiving both drugs.
The Australasian Leukaemia and Lymphoma Group
(ALLG) was conducting a large (>200 patients), rand-
omized clinical trial (ALLG MM6) in MM patients, who
had received high-dose therapy and autologous stem cell
transplantation (ASCT), to ascertain the efficacy and
safety of thalidomide and prednisolone maintenance
therapy compared to prednisolone maintenance therapy
post-transplantation. All patients were scheduled to
receive adjunctive zoledronic acid intravenously on a 4th-
weekly basis. The ALLG agreed to incorporate a safety sub-
study into the ALLG MM6 study to assess the pharmacok-
inetics of zoledronic acid and to monitor renal function in
patients randomized to receive prednisolone and
zoledronic acid alone or in combination with thalido-
mide, for up to 16 months.
Methods
From two Australian hospitals (The Alfred Hospital, Mel-
bourne and The Royal Melbourne Hospital) participating
in the ALLGMM6 study, a sample of 24 patients was
enrolled in this sub-study, with institutional ethical
approval and informed consent. All patients entered the
study 6–7 weeks after high-dose therapy and ASCT for
MM. Twelve patients were randomized to Arm 1: Thalido-
mide (100 mg nocte for 14 days, then 200 mg nocte to
end of study, if tolerated) and prednisolone (50 mg orally
on alternate days) in conjunction with zoledronic acid (4
mg intravenously every 4 weeks) and 12 were randomized
to Arm 2: prednisolone and zoledronic acid.
Patients' ages ranged from 41–68, with a median of 60 in
Arm 1 and 57 in Arm 2. There were 7 males and 5 females
in each Arm. No patient had progressive myeloma, ECOG
score > 2, renal, hepatic or severe marrow impairment at
study entry. All patients agreed to precautions related to
teratogenicity.
Thalidomide was provided as 50 mg tablets by Pharmion
Pty. Ltd. Zoledronic acid was provided as 4 mg concen-
trated liquid in vials, to be made up to 100 ml for intrave-
nous infusion over 15 minutes.
For renal safety monitoring, prior to each zoledronic acid
infusion, patients' serum creatinines were checked, and
any adverse events potentially related to zoledronic acid,
thalidomide or prednisolone were collected for up to 16
months on study.
For the pharmacokinetic study, venous blood samples (3
mL in heparinized tubes) were drawn from patients' arms
contra-lateral to the site of zoledronic acid infusions or
from central venous lines at the following times: Prior to
the 1st and 2nd doses of zoledronic acid (on Days 1 and 29)
and 1, 2, 4, 8, 24 and 48 hours after the 1st and 2nd doses.
Samples were centrifuged for 15 minutes at 2000 × G, and
the plasma transferred into a labelled tube that was frozen
below -20C. All pharmacokinetic samples were shipped in
dry ice to a central laboratory (Novartis Pharma AG, Rueil-
Malmaison, France) for analysis performed by a sensitive
radioimmunoassay for zoledronic acid [2].
One patient (from Arm 1) was excluded from analysis
because their pre-dose sample contained zoledronic acid,
and the reasons for this finding were unclear. There were
also five missing samples (3 from Arm 1 and 2 from Arm
2) for post-zoledronic acid pharmacokinetic analysis on
Day 29.
Non-parametric Wilcoxon rank-sum statistics were used
(by Covance Pty. Ltd, Canberra, Australia) to compare
non-compartmental pharmacokinetics (Cmax and AUC)
of each zoledronic acid infusion in patients who did or
did not also receive thalidomide. A parametric repeated-
measures t-test analysis was also conducted to assess PK
differences over 1st and 2nd infusions – although no
change in plasma PK of zoledronic acid was seen with
subsequent doses in an earlier (non-combination) PK
study [3]. The study was powered with 12 patients in each
group to have 80% chance of detecting (with p = 0.05) a
43% difference in PK of zoledronic acid in conjunction
with thalidomide, based on 27% interpatient variability
of Cmax for zoledronic acid in an earlier study [4].
Results
Pharmacokinetic analyses
Mean zoledronic acid plasma concentrations over 24
hours after infusion #1 in patients receiving zoledronic
acid in combination with thalidomide and prednisolone
(Arm 1; n = 11) or with prednisolone alone (Arm 2; n =
12) are shown in Figure 1. Mean Cmax after infusion #1
was 462 (± 135) ng/mL in Arm 1 and 409 (± 142) ng/mL.
Mean AUC(0–24 hr) was 639 (± 86) ng.h/mL in Arm 1
and 651 (± 140) ng.h/mL in Arm 2. Similar figures were
obtained after infusion #2 (not shown). No differences
were statistically significant by t-test (p = 0.05).
Renal safety
Mean serum creatinine values for up to 16 infusions of
zoledronic acid are shown in Figure 2. Again no differ-
ences between patients in Arm 1 (zoledronic acid, thalid-
omide and prednisolone) and Arm 2 (zoledronic acid
with prednisolone alone) were statistically significant.
Patients' creatinine clearance (calculated from serum cre-
atinine using Cockcroft & Gault formula) for arms 1 and
2 showed mean (SD) values of 104 +/- 27 mL/min (n =
11) and 106 +/- 27 mL/min (n = 12), respectively, at base-
line and 99 +/- 20 mL/min (n = 5) and 100 +/- 20 (n = 4),Page 2 of 4
(page number not for citation purposes)
BMC Clinical Pharmacology 2008, 8:2 http://www.biomedcentral.com/1472-6904/8/2respectively, after 13 infusions. The model estimated dif-
ference between arms 1 and 2, taking into account infu-
sion number and any interaction between treatment arms
and infusion, was 0.46 mL/min (P = 0.60), supporting the
conclusion of no effect on renal function by the addition
of thalidomide to the zoledronic acid treatment regimen.
Withdrawals from the sub-study were no different
between Arms 1 and 2, and largely due to progressive dis-
ease.
Discussion
This pharmacokinetic and renal safety sub-study of the
combination of zoledronic acid with thalidomide and
prednisolone in MM patients shows no likely PK interac-
tion between zoledronic acid and thalidomide (at doses
up to 200 mg/day). There was also no detectable increase
in serum creatinine in patients receiving combined ther-
apy for up to 16 months, unlike in previous case reports
[1].
MM patients who either a) do not receive concomitant
corticosteroid therapy, b) receive higher doses of thalido-
mide than 200 mg/day, or c) have underlying or intercur-
rent renal impairment could have interactions that were
not detected in this safety sub-study. Nevertheless, the
absence of PK interaction or renal impairment seen in this
safety sub-study is reassuring, given recent widespread
prescription of both thalidomide and zoledronic acid in
MM patients.
Conclusion
In myeloma patients receiving maintenance therapy, the
combination of zoledronic acid and thalidomide appears
to confer no additional renal safety risks over zoledronic
acid alone.
Competing interests
Drs Spencer and Roberts have received research funds and
honoraria from Novartis; Dr Copeman is a consultant to
Novartis; Drs Ravera, Cremers, Bilic, Schran and Lynch are
employees of Novartis, the manufacturer of zoledronic
acid.
Authors' contributions
AS, HS, MC and KL conceived the study. AS, AR and NK
carried out the clinical aspects of the study. TN contrib-
uted to the statistical design of the study and carried out
analyses of results. CR, SC, SB and HS carried out the
pharmacokinetic analyses of zoledronic acid. MC wrote
the manuscript.
a: Means (± standard deviation) of plasma concentrations of zoledronic acid after 1st infusion in Arm1 (n = 11) patie ts who received zoled onic c d, thalido ide and predn soloneFigu  1
a: Means (± standard deviation) of plasma concentra-
tions of zoledronic acid after 1st infusion in Arm1 (n = 
11) patients who received zoledronic acid, thalido-
mide and prednisolone. b: Means (± standard deviation) 
of plasma concentrations of zoledronic acid after 1st infusion 
in Arm2 (n = 12) patients who received zoledronic acid 
alone.
1
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Acknowledgements
The results of this safety sub-study were previously presented in part at the 
American Society of Hematology 2003 and 2004 meetings and at the Amer-
ican Society of Clinical Oncology 2004 meeting by Professor Spencer. This 
safety sub-study was funded by Novartis Pharma AG and conducted with 
the Australasian Leukaemia and Lymphoma Group and statistical analyses 
by Covance Pty. Ltd.
References
1. Jones SG, Dolan G, Lengyel K, Myers B: Severe increase in creat-
inine with hypocalcaemia in thalidomide-treated myeloma
patients receiving zoledronic acid infusions.  Br J Haematol
2002, 119(2):576-7.
2. Legay F, Gauron S, Deckert F, Gosset G, Pfaar U, Ravera C, Wiegand
H, Schran H: Development and validation of a highly sensitive
RIA for zoledronic acid, a new potent heterocyclic bisphos-
phonate, in human serum, plasma and urine.  J Pharm Biomed
Anal 2002, 30(4):897-911.
3. Chen T, Berenson J, Vescio R, Swift R, Gilchick A, Goodin S, LoRusso
P, Ma P, Ravera C, Deckert F, Schran H, Seaman J, Skerjanec A: Phar-
macokinetics and pharmacodynamics of zoledronic acid in
cancer patients with bone metastases.  J Clin Pharmacol 2002,
42(11):1228-36.
4. Berenson JR, Vescio RA, Rosen LS, VonTeichert JM, Woo M, Swift R,
Savage A, Givant E, Hupkes M, Harvey H, Lipton A: A Phase I dose-
ranging trial of monthly infusions of zoledronic acid for the
treatment of osteolytic bone metastases.  Clin Cancer Res 2001,
7(3):478-85.
Pre-publication history
The pre-publication history for this paper can be accessed
here:
http://www.biomedcentral.com/1472-6904/8/2/prepub
Means (± standard deviations) of serum creatinines prior to (up to 16) infusions of zoledronic acid in patients on Arm1 (dia-monds) [receiving zoledronic acid, thalidomide and ednisolone] and Arm 2 (triangles) [receiving zoledro ic acid alone]Figure 2
Means (± standard deviations) of serum creatinines prior to (up to 16) infusions of zoledronic acid in patients 
on Arm1 (diamonds) [receiving zoledronic acid, thalidomide and prednisolone] and Arm 2 (triangles) [receiv-
ing zoledronic acid alone]. Numbers of patients receiving each infusion are also shown, by reference to the scale on the 
right side.
0
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Crossref

Spencer, A

Roberts, A

Kennedy, N

Ravera, C

Cremers, S

Bilic, S

Neeman, T

Copeman, M

Schran, H

Lynch, K

University of Melbourne Institutional Repository

Renal safety of zoledronic acid with thalidomide in patients with myeloma: a pharmacokinetic and safety sub-study.

Development and validation of a highly sensitive RIA for zoledronic acid, a new potent heterocyclic bisphosphonate, in human serum, plasma and urine.

Severe increase in creatinine with hypocalcaemia in thalidomide-treated myeloma patients receiving zoledronic acid infusions.

Skerjanec A: Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases.

file:///data/core-remote/dit/data/Springer-OA/pdf/589/aHR0cDovL2xpbmsuc3ByaW5nZXIuY29tLzEwLjExODYvMTQ3Mi02OTA0LTgtMi5wZGY=.pdf

Renal safety of zoledronic acid with thalidomide in patients with myeloma: a pharmacokinetic and safety sub-study

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