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Originally published as JCO Early Release 10.1200/JCO.2008.19.3144 on November 3 2008 © 2008 American Society of Clinical Oncology.
Temsirolimus in Patients With Renal Cancer on Hemodialysis
National Institute for Cancer Research, Genova, Italy
Advanced Biotechnology Center, Genova and Center of Excellence for Biomedical Research, University of Genova, Italy
Sacro Cuore Don Calabria Hospital- Negrar, Verona, Italy
Socio-Sanitary Local Unity 22 –Bussolengo, Verona, Italy To the Editor: In a recent correspondence, Brugarolas et al1 reported a case of a man affected by renal cell carcinoma (RCC) treated with oral sirolimus. The authors found that oral sirolimus achieved trough levels comparable with those found after the administration of temsirolimus, and that sirolimus treatment was associated with a marked decrease in the rate of tumor progression. Moreover, the lack of available information about temsirolimus pharmacokinetics in patients on hemodialysis (HD) induced Brugarolas et al to suggest that "because temsirolimus is typically dosed weekly, the effects of hemodialysis on circulating drug levels are likely to be more profound with temsirolimus than for oral sirolimus, which is administered daily." Intravenous temsirolimus, a novel inhibitor of mammalian target of rapamycin, is approved for the treatment of advanced RCC. The principal metabolite of temsirolimus in humans is sirolimus, which also displays mammalian target of rapamycin inhibitory activity. Clinically relevant pharmacokinetic (PK) exposure to temsirolimus is considered to be a composite of both temsirolimus and sirolimus. Temsirolimus and sirolimus are both cleared by the liver and are extensively excreted in the feces.2 Because only small amounts are excreted in urine, dispositions in patients with RCC with nephrectomy or renal impairment are not expected to differ substantially. However, temsirolimus and sirolimus PK has not been studied in patients who are on HD. We conducted a PK study in two patients affected with metastatic RCC, and who were on HD, treated with temsirolimus. Patients received 25 mg temsirolimus as a weekly 30-minute intravenous infusion. Pretreatment with diphenhydramine 25 mg was given 30 minutes before the start of each temsirolimus infusion to prevent acute hypersensitivity reactions. Patients underwent HD 24, 72, and 144 hours after temsirolimus infusion. Temsirolimus and sirolimus were measured in whole blood samples of patients by reversed phase high-performance liquid chromatography mass spectrometry. During week 1 of treatment, blood samples were drawn for full PK profiling at 0 (predose), 0.5 (end of infusion), 1.5, 2.5, 5.5 hours, and before HD at 24, 72, and 144 hours. Three additional withdrawals were done to patients 1 hour after the end of hemodialysis at 28, 76, and 148 hours to compare drug values before and after HD. Temsirolimus and sirolimus PK data were analyzed using noncompartmental analysis techniques applying standard formulas.3 The following PK parameters were determined: the peak observed concentration (Cmax); the time to Cmax (tmax); terminal half-life (t1/2); area under the concentration versus time curve (AUC); total body clearance (CL); steady-state volume of distribution (Vdss); the uncorrected ratio of sirolimus to temsirolimus AUCs (AUCratio); and the algebraic sum of temsirolimus and sirolimus AUCs (AUCsum). Percent differences between drug concentrations before and after HD were calculated by the following formula: ((drug concentration before HD – drug concentration 1 hour after HD)/drug concentration before HD) x 100. The PK parameters of temsirolimus and sirolimus for the two patients after their initial dose of temsirolimus are reported as mean values in the (Table 1). Mean percent difference between drugs before and after hemodialysis were 6% and 10% for temsirolimus and sirolimus, respectively. Concentrations of temsirolimus and sirolimus immediately before HD were not statistically different from those obtained 1 hour after HD (P = .3 and P = .8, respectively, n = 6, t-test for paired data). According to Brugolas et al,1 "HD might only affect circulating levels of temsirolimus modestly, because of its relatively large molecular weight (1,030 Da), its large volume of distribution, and its being bound to blood-formed elements." However, our PK data on temsirolimus are the first evaluated in patient undergoing hemodialysis. These data obtained in two patients on hemodialysis, with RCC, are in good agreement with data reported in patients with normal renal function.4 Therefore, our data did not show any influence of HD on temsirolimus and sirolimus PK excluding the need of temsirolimus dose adjustments or the better use of daily oral sirolimus in patients affected by RCC and on HD.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
NOTES published online ahead of print at www.jco.org on November 3, 2008 REFERENCES
1. Brugarolas J, Lotan Y, Watumull L, et al: Sirolimus in metatastic renal cell carcinoma. J Clin Oncol 26:3457-3460, 2008 2. Torisel: package insert. Philadelphia, PA, Wyeth Pharmaceuticals Inc, 2007 3. Gibaldi M, Perrier D: Pharmacokinetics (ed 2). New York, NY, Marcel Dekker, 1982 4. Atkins MB, Hidalgo M, Stadler WM, et al: Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22:909-918, 2004
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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