Ibandronate: a clinical pharmacological and pharmacokinetic update

Ibandronate is a potent nitrogen-containing bisphosphonate. It has a strong affinity for bone mineral and potently inhibits osteoclast-mediated bone resorption. Ibandronate is effective for the treatment of hypercalcemia of malignancy, metastatic bone disease, postmenopausal osteoporosis, corticosteroid-induced osteoporosis, and Paget's disease. Oral ibandronate is rapidly absorbed (t(max) < 1 hour), with a low bioavailability (0.63%) that is further reduced (by up to 90%) in the presence of food. Ibandronate has a wide therapeutic index and is not metabolized and, therefore, has a low potential for drug interactions. Given its metabolic stability, ibandronate is eliminated from the blood by partitioning into bone (40%-50%) and through renal clearance (CL(R) approximately 60 mL/min). The CL(R) of ibandronate is linearly related to creatinine clearance. The sequestration of ibandronate in bone (V(D) > 90 L) results in a multiphasic elimination (t((1/2)) range approximately 10-60 hours), characterized by the slow release of ibandronate from the bone compartment. The potency of ibandronate and its sequestration into bone allow ibandronate to be developed as oral and intravenous injection formulations that can be administered with convenient extended between-dose intervals.     

Safety and efficacy of the new bisphosphonate ibandronate in the management of bone metastasis following rapid infusion

BACKGROUND: We evaluated the safety and efficacy of the new BP ibandronate, given as a rapid infusion. PATIENTS AND METHODS: We administered 4 mg of ibandronate as an intravenous infusion over 30 minutes. Thirty patients (16 breast cancers, 4 prostate cancers, 10 multiple myelomas) with bone metastases received 4 mg of ibandronate injected intravenously over 30 minutes in normal saline 0.9%, 250cc every 3 or 4 weeks. The patients were followed-up over 2 hours after infusion. A total of 198 infusions were administered over a period of 24 months and the patients were followed-up for long-term ibandronate-related side-effects, as well as for any potential clinical benefit. RESULTS: Following the first administration of ibantronate, serum levels of calcium, phosphate and alkaline phosphatase were significantly decreased and the difference was statistically significant (p < 0.001) for all three parameters examined. The reduced time of infusion (30 minutes vs 2 hours) did not correlate with any side-effects during or post-administration. Serum levels of creatinine and urea nitrogen did not increase significantly, while changes in temperature and blood pressure were not detected in the patients examined. With regard to efficacy, all the patients, after repeated administrations, reduced the doses of analgesics needed; 26 out of 30 patients had stable disease in the bones while 1 out of 30 patients had significant improvement of bone lesions in consecutive bone scans. CONCLUSION: Infusional administration of ibandronate is efficient in the management of hypercalcaemia of malignancy and it results in a reduced need for analgesics. The rapid infusion over 30 minutes is safe and could be given in the setting of a day care unit.     

High bone-binding capacity of ibandronate in hemodialysis patients

Bisphosphonates are a potential therapy for osteoclast-mediated bone disease, such as renal osteodystrophy. This study evaluated ibandronate bone-binding in patients with secondary hyperparathyroidism and renal osteodystrophy and examined whether there is a correlation with bone metabolism parameters. Sixteen patients with end-stage renal disease and secondary hyperparathyroidism receiving regular hemodialysis were recruited to this 12-week trial. Intravenous ibandronate 2 mg was administered for 5 min every 4 weeks directly after hemodialysis. Ibandronate levels were measured 15 min after infusion and at trough levels before the next hemodialysis. Serological markers of bone metabolism were also measured. After the first infusion, the peak ibandronate level was 154 +/- 75.1 ng/ml and the trough level was 2.7 +/- 1.7 ng/ml. At week 12, peak and trough ibandronate levels were 164.8 +/- 89.9 ng/ml and 3.2 +/- 2.6 ng/ml, respectively. Ibandronate bone uptake was 98.0% at first application and 98.4% at week 12. In patients with remaining diuresis, ibandronate urine excretion was < 0.001% of the administered dose. There was no correlation of ibandronate bone-binding with parameters of osteoclast activity or parathyroid hormone (PTH). The correlation with markers of osteoblast activity was significant but weak. Ibandronate had a bone-binding capacity of approximately 98% in hemodialysis patients. After repeated dosing ibandronate bone-uptake remained stable and was independent of osteoclast activity or PTH levels. Due to the high bone-binding of ibandronate in these patients, a 2 mg dose of intravenous ibandronate is equivalent to a 4-5 mg dose of ibandronate in patients with normal renal function.     

Renal function after long-term treatment with lithium.

Daily urine volumes, plasma creatinine concentrations, and creatinine clearance were measured in 106 patients with unipolar and bipolar affective disorders attending a "lithium" clinic. Urine volumes exceeded 3.51 in only six patients, plasma creatinine concentrations exceeded 150 mumol/1 (1.7 mg/100 ml) in only five, and creatinine clearance was below 50 ml/min in 16. Renal function was assessed by measuring creatinine clearance and renal tubular function, including response to 20 hours of water deprivation, in a representative sample of 30 patients from the lithium clinic and 30 psychiatric patients matched for age and sex who were taking other psychotropic drugs. Creatinine clearance and tubular function, including urine osmolality after water deprivation, were not significantly different between the two groups. Urinary excretion of arginine vasopressin (AVP), however, was much greater in the lithium-treated patients, who therefore had a diminished tubular responsiveness to AVP. The findings do not support suggestions that long-term lithium treatment results in seriously impaired renal function, renal damage, and polyuria. Compared with other series, however, the patients were being maintained with low serum lithium concentrations, which apparently area as effective prophylactically as higher concentrations.     

伊班磷酸钠治疗老年恶性肿瘤骨转移的临床研究

目的评价伊班磷酸钠治疗老年人恶性肿瘤骨转移的临床疗效及安全性。方法采用自身对照的方法，比较19例老年恶性肿瘤骨转移患者，治疗前后血清钙、磷、尿素氮、内生肌酐清除率及骨痛程度、溶骨性病灶的变化。结果治疗后校正血钙有一定程度下降，尿素氯、内生肌酐清除率无明显变化，单次治疗骨痛有效率78．9％。对溶骨性病灶治疗有效率100％，无严重不良反应。结论伊班磷酸钠可有效治疗恶性肿瘤骨转移，不良反应可以耐受。     

Steady state serum concentrations and renal clearance of digoxin in neonates,infants and children

Summary Steady state serum concentrations of digoxin were determined repeatedly in 34 infants with congenital heart disease. Simultaneous measurements of renal clearances of digoxin, creatinine and urea were obtained in 29 of the subjects. Serum digoxin concentrations were markedly higher in children under the age of 3 months than in those over this age, despite equal weight — adjusted 24 h doses. This finding was explained by a very rapid increase in renal digoxin clearance in the first 3 months — 32±7 ml/min/1.73m² at 1 week to 65.6±30 at 3 months. The subsequent increase in digoxin clearance was much slower, e.g. to 87.7±43 ml/min/1.73m² at 12 months. Renal clearance of digoxin was equally well correlated with creatinine clearance (r=0.87) as with urea clearance (r=0.83), but it exceeded that of creatinine in all age groups. The findings indicate that both glomerular and tubular function is involved in the renal elimination of digoxin in young children, and that development of renal elimination of the drug parallels that of the maturation of renal function in the early months of life. The neonate and infant with congestive heart failure display impaired ability to eliminate digoxin. The impairment lessens rapidly with the development of renal function over the first 3 months of life. Diminished doses of digoxin should be advocated in this age group if therapeutic serum concentrations of the drug are to be maintained and toxicity avoided.     

Pharmacokinetic study of cefsulodin in patients with kidney dysfunction

Seventeen patients with various grades of kidney function were injected each with cefsulodin (CFS) 1 g dissolved in 20 ml of saline. Serum and urine concentrations of CFS were determined using high performance liquid chromatography up to 24 hours after administration. Pharmacokinetic analysis was done using a two-compartment model. The results were discussed by comparing creatinine clearance (Ccr) values divided into 4 groups: greater than or equal to 70 ml/min (group I), 50-less than 70 ml/min (group II), 30-less than 50 ml/min (group III), and less than 30 ml/min (group IV). A delay in the disappearance of CFS from the blood was observed with a decrease in Ccr. Half-lives of CFS in blood (T 1/2 beta) were 1.03 hours (group I), 2.09 hours (group II), 3.44 hours (group III), and 4.52 hours (group IV). Serum clearance (Cls) and Ccr were found to be related with an equation: Cls = 1.60 x Ccr + 7.70. The correlation coefficient (r) was 0.881. Ccr and T 1/2 beta were found to be related with an equation: T 1/2 beta = 31.27 x Ccr-0.688, and the area under the curve (AUC) was found to be related to Ccr with AUC = 4,226 x Ccr-0.81. Urinary excretion rates up to 24 hours after administration were 84.4% (group I), 69.1% (group II), 67.5% (group III), and 56.5% (group IV). This means that CFS is excreted in urine with a relatively high recovery even in the case of low Ccr less than 30 ml/min.     

Disposition of recombinant human interleukin-10 in subjects with various degrees of renal function.

The pharmacokinetics of intravenously administered recombinant human interleukin-10 (rHuIL-10) were evaluated in 18 subjects with creatinine clearances (Clcr) between 2.7 and 116.7 mL/min/1.73 m2. Serum samples for rHuIL-10 were obtained over a 48-hour period after a single 25 micrograms/kg i.v. bolus infusion. AUC, total body clearance (Clp), and steady-state volume of distribution (Vdss) were derived by compartmental methods. Analysis of serum concentrations showed statistically significant group differences for log-transformed AUC and original scale Clp (p < 0.01). The AUC and effective half-life increased, while the mean Clp of rHuIL-10 decreased as renal function declined. A linear relationship between AUC and Clcr as well as Clp and Clcr demonstrates that the disposition of rHuIL-10 is altered in subjects with renal insufficiency. No serious adverse events were noted.     

Ibandronate, an experimental intravenous bisphosphonate for osteoporosis, bone metastases, and hypercalcemia of malignancy

Ibandronate is an experimental intravenous bisphosphonate under study for the prevention or treatment of osteoporosis and skeletal complications of bone metastases, as well as hypercalcemia of malignancy. To review the data on this drug, PubMed/MEDLINE was searched for pertinent studies in English; data from January 1986-October 2005 were reviewed. In preclinical studies, ibandronate was an extremely potent bisphosphonate compared with its predecessors and was active in all animal models of human postmenopausal and corticosteroid-associated osteoporosis. Similar to other bisphosphonates, ibandronate exhibits antitumor activity and prevents or reduces bone metastases. Forty to fifty percent of the dose is bound to bone; renal clearance of unchanged drug accounts for 70% of total body clearance. Early clinical trials demonstrated efficacy and tolerability of intravenous ibandronate in the prevention or treatment of postmenopausal and corticosteroid-associated osteoporosis when administered once every 3 months. Intravenous ibandronate also reduces skeletal complications of bone metastases, including pain, although the cumulative dose used is much higher than that used in osteoporosis, as the drug is administered every 3-4 weeks. Single doses of intravenous ibandronate are probably also effective in the treatment of hypercalcemia of malignancy. The major tolerability issue with intravenous bisphosphonates is renal safety, thus the drugs generally require infusion (e.g., 0.25 hr for zoledronic acid, 2-24 hrs for pamidronate). However, intravenous ibandronate can be administered by bolus injection over a few minutes without an elevated risk of nephrotoxicity. The experimental intravenous dosage is 2 mg every 3 months for treatment or prevention of osteoporosis, and 2-6 mg every 3-4 weeks or in a single dose for treatment of bone metastases or hypercalcemia of malignancy, respectively. Ibandronate can be used in the presence of severe renal impairment with proper dosage adjustment. The drug will be an interesting addition to the available drugs for osteoporosis, bone metastases, and hypercalcemia of malignancy. Studies of intravenous ibandronate as an adjunctive treatment for cancers that tend to metastasize to bone are under way. Whether intravenous ibandronate will be a therapeutic advance is best answered by randomized, controlled trials. These are ongoing and should provide data with which to make better-informed choices concerning intravenous bisphosphonates.     

Pharmacokinetics of ceftriaxone in subjects with renal insufficiency

The pharmacokinetics of ceftriaxone was studied in 14 men and women volunteers with renal insufficiency. Subjects were grouped by renal function: those with end-stage renal disease (CLcr less than 15 mL/min/1.73 sq m) but not receiving dialysis, those with severe renal insufficiency (CLcr 16-30 mL/min/1.73 sq m), and those with moderate renal insufficiency (CLcr 31-60 mL/min/1.73 sq m). Ceftriaxone 1 g as the sodium salt was administered by i.v. infusion over 30 minutes, and blood and urine samples were collected before and up to 48 hours after drug administration. The pharmacokinetic data were described using a nonlinear least-squares computer program. For volunteers with a creatinine clearance of less than 15 mL/min/1.73 sq m, the mean half-life was 15.6 hours. For subjects with a creatinine clearance of 31-60 mL/min/1.73 sq m, the mean half-life was 11.9 hours. Plasma ceftriaxone concentrations measured at the conclusion of the infusion (mean peak concentration 122 +/- 53.1 micrograms/mL) or 24 hours after the infusion (mean concentration 20.2 +/- 6.14 micrograms/mL) were similar in each study group. A dose of ceftriaxone 1 g every 24 hours in patients with renal insufficiency is probably adequate for inhibiting most susceptible gram-positive and gram-negative microorganisms.     

Pharmacokinetics of the loop diuretic piretanide in renal failure

Summary Piretanide 60 mg was administered intravenously over 30 min to 15 men with different degrees of renal failure. The mean piretanide serum concentration at the end of the infusion period was 5.72±1.51 µg/ml. Serum piretanide concentration-time curves declined biexponentially and 24 hours after medication the serum level had fallen to less than twice the detection limit. The terminal half-life ranged from 1.63 to 3.44 h. A relationship to creatinine clearance was not demonstrable. The mean metabolic clearance of piretanide was 107.7±47.6 ml/min/1.73 m² body surface area and was the same as that reported for healthy subjects. The renal clearance of piretanide ranged from 3.33 to 43.9 ml/min/1.73 m² body surface area and very closely correlated with the creatinine clearance (p<0.01). Its renal clearance dependend principally on active secretion of the drug into the tubule, and glomerular filtration appeared unimportant. There was a close relationship between the amount of piretanide excreted in the urine and the creatinine clearance. Because the diuretic effect of piretanide depends on the concentration of the drug in the tubule, the observed correlation might be of use in evaluating the appropriate dosage of piretanide in patients with renal failure. The present data suggest that single daily doses of piretanide will not result in accumulation, even when high doses are administered to patients with advanced renal failure.     

Pharmacokinetics of cerivastatin in renal impairment are predicted by low serum albumin concentration rather than by low creatinine clearance

The influence of renal impairment on the clearance of the new HMG-CoA reductase inhibitor cerivastatin was evaluated. A single oral dose of 300 microg cerivastatin was given to 18 patients with different degrees of renal impairment and 6 healthy controls. Concentrations of total cerivastatin, its fraction unbound, and the total concentrations of the active metabolites M1 and M23 were measured in plasma. Serum concentrations of unbound cerivastatin were calculated for each individual from the concentration of total cerivastatin and cerivastatin's fraction unbound at t = 2.5 hours. In contradiction to what had been expected, renal impairment significantly influenced the pharmacokinetics of cerivastatin. The best correlation to the AUC and Cmax of unbound cerivastatin was found with serum albumin concentration. Also, serum albumin concentration was the only factor significantly correlated to t 1/2 of cerivastatin. Significant but slighter correlation with the AUC and Cmax of unbound cerivastatin was also observed for creatinine clearance and cerivastatin's fraction unbound, while no correlation was observed with total plasma protein. No significant correlation of creatinine clearance, serum albumin concentration, fu, or total plasma protein concentration with the AUC and Cmax of total cerivastatin or the AUC, Cmax or t 1/2 of M1 and M23 was observed. The authors conclude that low serum albumin concentration rather than low creatinine clearance predicts the pharmacokinetics of cerivastatin in renal impairment.     

Pharmacokinetics of sisomicin in patients with normal and impaired renal function; its efficacy in urinary tract infection

Summary Serum concentration, biological half-life, distribution space and serum clearance of sisomicin, a new aminoglycoside antibiotic, have been studied in twenty-three patients in comparison with the pharmacokinetics of¹²⁵I-labelled iothalamate, a compound only filtered by the kidney. 10 patients had normal or borderline abnormal serum creatinine (<1,5 mg/100 ml), 8 had various degrees of renal insufficiency (serum creatinine 1.7 – 9.6 mg/100 ml) and 6 were being treated by intermittent haemodialysis. After intravenous injection of sisomicin 1 mg/kg body weight in patients with normal or borderline renal function its half-life was 3.5 h, very similar to that of iothalamate, 3.2 h. The mean distribution space was 20.1 % per cent of body weight; iothalamate, 23.7 %. In patients with renal insufficiency there was a positive correlation between serum creatinine level and the half-life of sisomicin, and an even stronger correlation between the clearances of iothalamate and sisomicin. In patients dependent on haemodialysis, the mean serum half-life between dialysis was 40 h, compared to approximately 100 hours for iothalamate, which implies additional extrarenal clearance or tubular secretion of sisomicin. The results of pharmacokinetic studies indicated that a regime of sisomicin 1 mg/kg every 8 to 12 hours in patients with normal renal function would result in serum and urine levels sufficiently high to treat most urinary tract infections. In patients with impaired renal function the dosage interval should be increased according to the serum creatinine level, and in patients dependent on haemodialysis one standard dose at the end of each dialysis period should suffice. 9 patients with a chronic urinary tract infection severely complicated by an underlying disease were treated according to this dosage regimen with a satisfactory bacteriological and clinical result. No adverse reactions or signs of accumulation were observed.     

Effect of renal function on risedronate pharmacokinetics after a single oral dose

AIMS: To determine the relationship between risedronate pharmacokinetics and renal function. METHODS: Risedronate was administered to adult men and women (n=21) with various degrees of renal function (creatinine clearance 15-126 ml min-1 ) as a single oral dose of 30 mg. Serum samples were obtained for 72 h after dosing, and urine samples were collected for 72 h after dosing and then periodically for 6 weeks. Risedronate concentrations were determined using an enzyme-linked immunosorbent assay (ELISA). Risedronate serum concentration-time and urinary excretion rate-time profiles were analysed simultaneously using nonlinear regression. RESULTS: Renal clearance and volume of distribution were linearly related to creatinine clearance (r2=0.854, P<0.001; and r2=0.317, P<0.01, respectively). Decreases in predicted renal clearance and volume of distribution of 82 and 69%, respectively, were observed when creatinine clearance decreased from 120 to 20 ml min-1. A 64% decrease in predicted oral clearance was observed when creatinine clearance decreased from 120 to 20 ml min-1 (P=0.064). Iohexol clearance, a predictor of renal function, produced similar results to those observed with creatinine clearance. Risedronate was well tolerated by the study population. CONCLUSIONS: Risedronate renal clearance was significantly related to a decrease in renal function. There was a consistent reduction in oral clearance with a decrease in creatinine clearance. However, based on the regression analysis, generally no dosage adjustment appears to be necessary for most patients with mild or moderate renal impairment (creatinine clearance >20 ml min-1 ).     

Clopidogrel activities in patients with renal function impairment

OBJECTIVES: To assess the tolerability, pharmacodynamic effects and pharmacokinetic parameters after repeated doses of clopidogrel (Plavix((R))) in patients with moderate or severe renal failure. PATIENTS: Eight patients with severe renal failure (endogenous creatinine clearance 5 to 15 ml/min) and eight patients with moderate renal impairment (endogenous creatinine clearance 30 to 60 ml/min) were included. STUDY DESIGN: An open, uncontrolled, parallel-group study over 8 days' administration of 75mg once-daily clopidogrel. METHODS: Measurement of changes in ADP-induced platelet aggregation and skin bleeding time and of plasma concentrations and urinary excretion of clopidogrel and its main metabolite, SR 26334. Assessment of clinical tolerance and serial haematological and biochemical investigations. RESULTS: At the end of the dosage period, platelet aggregation was equally inhibited, by about 25%, and bleeding time equally extended, by a factor of about 2, in the two groups. There were no tolerability concerns. Maximum plasma concentration (C(max)) and time to reach C(max ) (t(max)) for clopidogrel were not significantly different between the two groups. SR 26334 excreted into the urine and renal clearance rate were significantly lower in the severely impaired group, while plasma elimination half-lives were not significantly different. C(max) and t(max) did not differ significantly between the two groups, but trough levels and area under the plasma concentration-time curve from zero to 24 hours (AUC(0-24h)) after the last dose were significantly higher in the moderately impaired group. CONCLUSIONS: Clopidogrel 75mg once daily was well tolerated in patients with either moderate or severe renal failure, and provided good inhibition of ADP-induced platelet aggregation without excessive extension of bleeding time. Dose adjustment in such patients does not appear to be required.     

Serum beta2-microglobulin in the assessment of renal function.

This study was undertaken to compare the serum beta2-microglobulin (beta2-m) as a test of renal function with the plasm creatinine and the glomerular filtration rate as estimated by the 24 hour endogenous creatinine clearance and the single injection 51Cr EDTA clearance method. Of the 33 patients with a variety of renal diseases and the four healthy volunteers studied, an excellent correlation was found between the serum beta2-m concentration (measured by radioimmunoassay) and the plasma creatinine, the creatinine clearance and the 51Cr EDTA clearance. When a more simple and less expensive method becomes available for the measurement of serum beta2-m it could prove a useful test of renal function. The assay of beta2-m in the urine could prove valuable for assessing whether proteinuria is glomerular or tubular in origin.     

Pharmacokinetics of the oral direct renin inhibitor aliskiren alone and in combination with irbesartan in renal impairment

BACKGROUND: Aliskiren is an orally active direct renin inhibitor approved for the treatment of hypertension. This study assessed the effects of renal impairment on the pharmacokinetics and safety of aliskiren alone and in combination with the angiotensin receptor antagonist irbesartan. METHODS: This open-label study enrolled 17 males with mild, moderate or severe renal impairment (creatinine clearance [CL(CR)] 50-80, 30-49 and <30 mL/minute, respectively) and 17 healthy males matched for age and bodyweight. Subjects received oral aliskiren 300 mg once daily on days 1-7 and aliskiren coadministered with irbesartan 300 mg on days 8-14. Plasma aliskiren concentrations were determined by high-performance liquid chromatography/tandem mass spectrometry at frequent intervals up to 24 hours after dosing on days 1, 7 and 14. RESULTS: Renal clearance of aliskiren averaged 1280 +/- 500 mL/hour (mean +/- SD) in healthy subjects and 559 +/- 220, 312 +/- 75 and 243 +/- 186 mL/hour in patients with mild, moderate and severe renal impairment, respectively. At steady state (day 7), the geometric mean ratios (renal impairment : matched healthy volunteers) ranged from 1.21 to 2.05 for the area under the plasma concentration-time curve (AUC) over the dosage interval tau (24h) [AUC(tau)]) and from 0.83 to 2.25 for the maximum observed plasma concentration of aliskiren at steady state. Changes in exposure did not correlate with CL(CR), consistent with an effect of renal impairment on non-renal drug disposition. The observed large intersubject variability in aliskiren pharmacokinetic parameters was unrelated to the degree of renal impairment. Accumulation of aliskiren at steady state (indicated by the AUC from 0 and 24 hours [AUC(24)] on day 7 vs day 1) was similar in healthy subjects (1.79 [95% CI 1.24, 2.60]) and those with renal impairment (range 1.39-1.99). Coadministration with irbesartan did not alter the pharmacokinetics of aliskiren. Aliskiren was well tolerated when administered alone or with irbesartan. CONCLUSIONS: Exposure to aliskiren is increased by renal impairment but does not correlate with the severity of renal impairment (CL(CR)). This is consistent with previous data indicating that renal clearance of aliskiren represents only a small fraction of total clearance. Initial dose adjustment of aliskiren is unlikely to be required in patients with renal impairment.     

Preclinical and clinical efficacy of the bisphosphonate ibandronate in cancer treatment

Bisphosphonates, like ibandronate (Bondronat), represent the mainstay of treatment for metastatic bone disease. Ibandronate selectively binds to bone mineral and prevents osteoclast-mediated skeletal destruction. This review describes the preclinical and clinical profiles of ibandronate for treatment of cancer metastatic to bone. In preclinical studies ibandronate reduced metastatic processes and tumor growth, induced tumor cell apoptosis, decreased bone pain, and enhanced biomechanical indices. Skeletal destruction was completely prevented with ibandronate, and this directly correlated with histomorphometry and markers of bone turnover. Ibandronate efficacy in combination with anti-cancer therapies is discussed. Preclinical studies demonstrated that ibandronate does not compromise safety, including renal health. Intravenous and oral ibandronate had comparable efficacy in three Phase III clinical trials. Ibandronate achieved significant risk reductions in the incidence of skeletal-related events and bone pain. In additional clinical studies, ibandronate reduced markers of bone turnover. Furthermore, loading-dose ibandronate rapidly reduced bone pain in Phase II trials. Adjuvant trials are ongoing. The clinical safety profile (including a 4-year follow-up study) has demonstrated renal health is maintained with ibandronate. Overall, ibandronate preserves skeletal integrity, has a favorable safety profile, maintains renal function, and can rapidly reduce and maintain bone pain below baseline levels in patients with cancer metastatic to bone.     

Pharmacokinetics in renally impaired subjects of NXY-059, a nitrone-based,free-radical trapping agent developed for the treatment of acute stroke

OBJECTIVE: NXY-059 is a nitrone-based, free-radical trapping agent being developed for the treatment of acute ischaemic stroke. Elimination of NXY-059 is primarily renal. The objective of the study was to investigate the pharmacokinetics of NXY-059 in subjects with renal impairment. METHODS: Twenty-four subjects with a glomerular filtration rate (GFR) ranging from 19 ml/min to 100 ml/min received NXY-059 intravenously over a 24-h period. Drug in plasma and urine was measured for 72 h. One-hour loading infusion rates were proportional to body weight, while maintenance infusion rates were proportional to GFR. Target plasma levels were 60 micro mol/l for subjects with mild (GFR 50-100 ml/min) and moderate (GFR 30-49 ml/min) renal impairment, and 30 micro mol/l for subjects with severe renal impairment (GFR <30 ml/min). GFR was measured as sinistrin clearance. RESULTS: The data indicated no tolerability or safety concerns with NXY-059. The half-life, which normally is approximately 2-4 h, was in the order of 10-12 h in subjects with moderate and severe renal impairment. The distribution parameters steady-state volume of distribution (V(ss)) and unbound fraction in plasma at 13-15 l and 0.53-0.58, respectively, were virtually the same as previously observed in healthy subjects. Plasma clearance of NXY-059, which ranged from 9 ml/min to 76 ml/min, was directly proportional to kidney function (GFR) with no discernible contribution by non-renal clearance. The correlation coefficient squared (r(2)) was 0.93, both when the renal function parameter was GFR and when it was creatinine clearance estimated from serum creatinine, age, weight and sex. CONCLUSION: Non-renal elimination of NXY-059 appeared to be insignificant even in subjects with low renal capacity. Patients with renal impairment should have their dose of NXY-059 adjusted for renal function, conveniently assessed from serum creatinine.