Pharmacokinetics of Clofarabine in Patients With High-Risk Inherited Metabolic Disorders Undergoing Brain-Sparing Hematopoietic Cell Transplantation
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.The Journal of Clinical Pharmacology (Impact Factor: 2.48). 05/2011; 51(5):679-86. DOI: 10.1177/0091270010372519
Clofarabine, a newer purine analog with reduced central nervous system toxicity, may prove advantageous in hematopoietic cell transplantation in patients for whom neurotoxicity is a natural part of disease progression. This study evaluated clofarabine pharmacokinetics in adult and pediatric patients undergoing hematopoietic cell transplantation for the treatment of high-risk, inherited metabolic disorders. Clofarabine (40 mg/m(2)/d) was administered intravenously on days -7 to -3. Kinetic sampling occurred with doses 1 and 5, along with a single level collected on day of transplant (day(0)). Sixteen patients were studied with a median (range) age and body surface area (BSA) of 7.5 years (0.5-43) and 0.94 m(2) (0.31-2.3), respectively. Clofarabine area under the concentration-time curve from time 0 to infinity was 931 ng·h/mL (685-1876), maximum concentration was 226 ng/mL (162-600), and minimum concentration was 3.2 ng/mL (1.7-5.6). Clofarabine clearance was 1.6 L/h/kg (0.7-2.4) and weakly correlated with weight (r(2) = 0.33) and BSA (r(2) = 0.26). No difference in plasma concentrations was found between dose 1 and dose 5 (all P > .05). All concentrations were below the limit of quantification (1 ng/mL) on day(0) in patients with normal renal function. Variability in clofarabine clearance was approximately 3-fold and was not adequately explained by covariates describing renal function and body size. In patients with adequate renal function, no drug accumulation occurs with consecutive daily dosing.
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ABSTRACT: Fludarabine, clofarabine, and cladribine are anticancer agents which are analogues of the purine nucleoside adenosine. These agents have been associated with cardiac and neurological toxicities. Because these agents are analogues of adenosine, they may act through adenosine receptors to elicit their toxic effects. The objective of this study was to evaluate the ability of cytotoxic nucleoside analogues to bind and activate adenosine receptor subtypes (A1, A2A, A2B, and A3). Radioligand binding studies utilizing Chinese hamster ovary cells, stably transfected with adenosine A1, A2A, or A3 receptor subtype, were used to assess the binding affinities of these compounds, whereas adenylyl cyclase activity was used to assess the binding to A2B receptors. Clofarabine and cladribine both bound to the A2A receptor with a K i of 17 and 15 μM, respectively. Clofarabine was the only adenosine analogue to bind to the A3 receptor with a K i of 10 μM, and none of these compounds bound to the A2B receptor. Results show that clofarabine, cladribine, and fludarabine bind to the A1 receptor. In addition, clofarabine, cladribine, and fludarabine were A1 agonists (IC50 3.1, 30, and 30 μM, respectively). Neither pyrimidine nucleoside analogues gemcitabine nor cytarabine associated with any of the adenosine receptor subtypes (K i > 100μM). This is the first report of an interaction between all adenosine receptor subtypes and chemotherapeutic nucleoside analogues commonly used in the treatment of cancer. Therefore, activation of these receptors may be at least one mechanism through which fludarabine-associated toxicity occurs.Archiv für Experimentelle Pathologie und Pharmakologie 01/2012; 385(5):519-25. DOI:10.1007/s00210-011-0719-6 · 2.47 Impact Factor
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ABSTRACT: Melphalan remains the most widely used agent in preparative regimens for hematopoietic stem cell transplantation (SCT). From its initial discovery more than 50 years ago, it has been gradually incorporated in the conditioning regimens for both autologous and allogeneic transplantations because of its myeloablative properties and broad antitumor effects as a DNA alkylating agent. Melphalan remains the mainstay conditioning for multiple myeloma and lymphomas, and it has been used successfully in preparative regimens of a variety of other hematological and nonhematological malignancies. The addition of newer agents to conditioning, such as bortezomib or lenalidomide for myeloma or clofarabine for myeloid malignancies, may improve antitumor effects for transplantation, whereas melphalan in combination with alemtuzumab may represent a backbone for future cellular therapy because of reliable engraftment and low toxicity profile. This review summarizes the development and the current use of this remarkable drug in hematopoietic SCT.Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 08/2012; 19(3). DOI:10.1016/j.bbmt.2012.08.011 · 3.40 Impact Factor
- Journal of Clinical Oncology 05/2013; 31(19). DOI:10.1200/JCO.2012.45.4728 · 18.43 Impact Factor
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