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Pharmacokinetics of ibandronate in myeloma patients with renal insufficiancy
S68
ABSTRACTS / Bone 38 (2006) S65 – S87
one possible mechanism for these reactions. Similar to the acute phase reaction, these immune changes normally disappear after 48 hours. Previous studies have shown that kidney transplant recipients treated with immunosuppressive therapy and ibandronate for bone protection have a lower rejection rate than those treated with immunosuppressive therapy and placebo. This suggests that there may be long-term changes in the immune system occurring with ibandronate treatment. Aims: To study the long term changes in the cellular immune system during ibandronate treatment in dialysis patients. As these patients are not normally treated with immunosuppressive agents or cytotoxic agents, which can cause changes in the cellular immune system, they are an eligible population for such a study. Methods: In this open-label trial, 16 patients with end-stage renal disease receiving regular hemodialysis were recruited. All patients were treated with ibandronate 2mg every 4 weeks for renal osteopathy, which correlates to ibandronate 4 – 5 mg in patients with normal renal function. The cellular immune system was investigated before first ibandronate infusion and the measurement was repeated at weeks 2, 4 and 48. The following parameters were measured by blood count differentiation: leucocytes, granulocytes lymphocytes, monocytes. Lymphocyte subtypes were measured by flow cytometry: B-lymphocytes (CD3+/CD19+), T-helper cells (CD3+/CD4+), T-suppressor cells (CD3+/CD8+), natural killer (NK)-cells (CD3+/CD16+ 56+), helper-inducer cells (CD4+/CD29+), activated T-cells (CD3+/HLA-DR+), activated T-lymphocytes (CD3+/CD25+), naive T-cells (CD3+/CD45RA+) and memory-T-lymphocytes (CD3+/CD45RO+). Results: Twelve patients completed the study and were evaluated. One patient dropped out because of flu-like symptoms with muscle pain after the first ibandronate infusion; however this was well controlled with paracetamol. Three patients died due to concomitant diseases (diabetes and cardiovascular events). There were no statistically significant differences in cellular immunity over time as measured in weeks 0, 2, 4 and 48. Summary/Conclusions: In this small-pilot study of dialysis patients receiving ibandronate, no changes in the cellular immune system were observed over time. Changes in different lymphocyte subtypes, which occur in the acute phase reaction after first infusion, were not seen.
Methods: In an open-label study of patients with multiple myeloma (n = 40, creatinine clearance 8203 ml/min), intravenous ibandronate 6mg was administered over 30 minutes. Ibandronate serum levels were measured over 24 hours. AUC of serum ibandronate levels were calculated. Renal function deterioration was graded depending on creatinine clearance (grade 0: 80, 1: 50 – 79, 2: 30 – 49, 3: <30 ml/min). Total ibandronate renal clearance and total body clearance were calculated. Results: At baseline, 7 patients had normal renal function and 33 patients had varying degrees of existing renal insufficiency (segmented into 4 grades). Mean proteinuria was 1801 T 2154 mg/24 hours. There was a statistically significant positive correlation between ibandronate elimination and creatinine clearance (r = 0.83; P < 0.001). The AUC for ibandronate was not significantly different over the four grades of creatinine clearance (51.9 T 20.9; 53.4 T 10.6; 65.6 T 22.6; 66.6 T 27.9 Ag/1440 min). There was also no significant change in total body clearance in the different stages of renal insufficiency. The amount of proteinuria had no significant influence on the excretion of ibandronate. Conclusions: In this study, the elimination of ibandronate corelated with renal function; however, the AUC of ibandronate serum levels did not increase significantly. This may indicate that the amount of ibandronate bound to bone increases with renal insufficiency. In patients with varying degrees of renal insufficiency, intravenous ibandronate was well tolerated.
doi:10.1016/j.bone.2006.01.011
66 Intravenous and oral ibandronate have better safety and tolerability profiles than zoledronic acid: Evidence from comparative phase III trials B. Bergstro¨m a, M. Lichinitser b, J.J. Body c a Hoffmann-La Roche Inc., Nutley, New Jersey, USA b NN Blokhin Russian Cancer Research Center, Moscow, Russia c Institut Jules Bordet, Universite´ Libre de Bruxelles, Brussels, Belgium
doi:10.1016/j.bone.2006.01.010
65 Pharmacokinetics of ibandronate in myeloma patients with renal insufficiency R. Bergner , B. Weiss, M. Hoffmann, D.M. Henrich, M. Uppenkamp Medizinische Klinik A, Klinikum Ludwigshafen, Germany Background: Bisphophonates are either bound into the bone or excreted rapidly by the kidney, therefore renal function has an important influence on the pharmacokinetics of bisphosphonates.
Ibandronate is a single-nitrogen, non-cyclic bisphosphonate available in intravenous and oral formulations. In phase III trials, both formulations had safety profiles comparable to placebo. Here, safety data from two comparative, open-label, randomized phase III trials are reported. Patients received ibandronate or zoledronic acid for 12 weeks. In trial A, the ibandronate group received intravenous ibandronate 6 mg on Day 1 (15-minute infusion) then daily oral ibandronate 50 mg from Day 2 onwards. In trial B, ibandronate-treated patients received daily oral ibandronate 50 mg only. Comparative treatment in both trials was intravenous zoledronic acid 4 mg every 3 –4 weeks. In trial A, patients with breast cancer or multiple myeloma were recruited (n = 77); trial B recruited
ABSTRACTS / Bone 38 (2006) S65 – S87
one possible mechanism for these reactions. Similar to the acute phase reaction, these immune changes normally disappear after 48 hours. Previous studies have shown that kidney transplant recipients treated with immunosuppressive therapy and ibandronate for bone protection have a lower rejection rate than those treated with immunosuppressive therapy and placebo. This suggests that there may be long-term changes in the immune system occurring with ibandronate treatment. Aims: To study the long term changes in the cellular immune system during ibandronate treatment in dialysis patients. As these patients are not normally treated with immunosuppressive agents or cytotoxic agents, which can cause changes in the cellular immune system, they are an eligible population for such a study. Methods: In this open-label trial, 16 patients with end-stage renal disease receiving regular hemodialysis were recruited. All patients were treated with ibandronate 2mg every 4 weeks for renal osteopathy, which correlates to ibandronate 4 – 5 mg in patients with normal renal function. The cellular immune system was investigated before first ibandronate infusion and the measurement was repeated at weeks 2, 4 and 48. The following parameters were measured by blood count differentiation: leucocytes, granulocytes lymphocytes, monocytes. Lymphocyte subtypes were measured by flow cytometry: B-lymphocytes (CD3+/CD19+), T-helper cells (CD3+/CD4+), T-suppressor cells (CD3+/CD8+), natural killer (NK)-cells (CD3+/CD16+ 56+), helper-inducer cells (CD4+/CD29+), activated T-cells (CD3+/HLA-DR+), activated T-lymphocytes (CD3+/CD25+), naive T-cells (CD3+/CD45RA+) and memory-T-lymphocytes (CD3+/CD45RO+). Results: Twelve patients completed the study and were evaluated. One patient dropped out because of flu-like symptoms with muscle pain after the first ibandronate infusion; however this was well controlled with paracetamol. Three patients died due to concomitant diseases (diabetes and cardiovascular events). There were no statistically significant differences in cellular immunity over time as measured in weeks 0, 2, 4 and 48. Summary/Conclusions: In this small-pilot study of dialysis patients receiving ibandronate, no changes in the cellular immune system were observed over time. Changes in different lymphocyte subtypes, which occur in the acute phase reaction after first infusion, were not seen.
Methods: In an open-label study of patients with multiple myeloma (n = 40, creatinine clearance 8203 ml/min), intravenous ibandronate 6mg was administered over 30 minutes. Ibandronate serum levels were measured over 24 hours. AUC of serum ibandronate levels were calculated. Renal function deterioration was graded depending on creatinine clearance (grade 0: 80, 1: 50 – 79, 2: 30 – 49, 3: <30 ml/min). Total ibandronate renal clearance and total body clearance were calculated. Results: At baseline, 7 patients had normal renal function and 33 patients had varying degrees of existing renal insufficiency (segmented into 4 grades). Mean proteinuria was 1801 T 2154 mg/24 hours. There was a statistically significant positive correlation between ibandronate elimination and creatinine clearance (r = 0.83; P < 0.001). The AUC for ibandronate was not significantly different over the four grades of creatinine clearance (51.9 T 20.9; 53.4 T 10.6; 65.6 T 22.6; 66.6 T 27.9 Ag/1440 min). There was also no significant change in total body clearance in the different stages of renal insufficiency. The amount of proteinuria had no significant influence on the excretion of ibandronate. Conclusions: In this study, the elimination of ibandronate corelated with renal function; however, the AUC of ibandronate serum levels did not increase significantly. This may indicate that the amount of ibandronate bound to bone increases with renal insufficiency. In patients with varying degrees of renal insufficiency, intravenous ibandronate was well tolerated.
doi:10.1016/j.bone.2006.01.011
66 Intravenous and oral ibandronate have better safety and tolerability profiles than zoledronic acid: Evidence from comparative phase III trials B. Bergstro¨m a, M. Lichinitser b, J.J. Body c a Hoffmann-La Roche Inc., Nutley, New Jersey, USA b NN Blokhin Russian Cancer Research Center, Moscow, Russia c Institut Jules Bordet, Universite´ Libre de Bruxelles, Brussels, Belgium
doi:10.1016/j.bone.2006.01.010
65 Pharmacokinetics of ibandronate in myeloma patients with renal insufficiency R. Bergner , B. Weiss, M. Hoffmann, D.M. Henrich, M. Uppenkamp Medizinische Klinik A, Klinikum Ludwigshafen, Germany Background: Bisphophonates are either bound into the bone or excreted rapidly by the kidney, therefore renal function has an important influence on the pharmacokinetics of bisphosphonates.
Ibandronate is a single-nitrogen, non-cyclic bisphosphonate available in intravenous and oral formulations. In phase III trials, both formulations had safety profiles comparable to placebo. Here, safety data from two comparative, open-label, randomized phase III trials are reported. Patients received ibandronate or zoledronic acid for 12 weeks. In trial A, the ibandronate group received intravenous ibandronate 6 mg on Day 1 (15-minute infusion) then daily oral ibandronate 50 mg from Day 2 onwards. In trial B, ibandronate-treated patients received daily oral ibandronate 50 mg only. Comparative treatment in both trials was intravenous zoledronic acid 4 mg every 3 –4 weeks. In trial A, patients with breast cancer or multiple myeloma were recruited (n = 77); trial B recruited