Pharmacokinetics of Clofarabine in Patients With High-Risk Inherited Metabolic Disorders Undergoing Brain-Sparing Hematopoietic Cell Transplantation
ABSTRACT 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: A method for quantification of fludarabine (FDB) and clofarabine (CFB) in human plasma was developed with an API5000 LC-MS/MS system. FDB and CFB were extracted from EDTA plasma samples by protein precipitation with trichloroacetic acid. Briefly, 50μL plasma sample was mixed with 25μL internal standard (50ng/mL aqueous 2-Cl-adensosine) and 25μL 20% trichloroacetic acid, centrifuged at 25,000×g (20,000rpm) for 3min, and then transfered to an autosampler vial. The extracted sample was injected onto an Eclipse extend C18 column (2.1mm×150mm, 5μm) and eluted with 1mM NH4OH (pH 9.6) - acetonitrile in a gradient mode. Electrospray ionization in positive mode (ESI(+)) and multiple reaction monitoring (MRM) were used, and ion pairs 286/134 for FDB, 304/170 for CFB and 302/134 for the internal standard were selected for quantification. The retention times were typically 3.72min for FDB, 4.34min for the internal standard, 4.79min for CFB. Total run time was 10min per sample. Calibration range was 0.5-80ng/mL for CFB and 2-800ng/mL for FDB. The method was applied to a clinical pharmacokinetic study in pediatric patients.Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 05/2014; 960C:194-199. DOI:10.1016/j.jchromb.2014.04.045 · 2.69 Impact Factor
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ABSTRACT: Clofarabine is a novel purine nucleoside analogue with immunosuppressive and anti-leukemic activity in acute lymphoblastic and myeloid leukemia (AML, ALL). This retrospective study was performed to evaluate the feasibility and anti-leukemic activity of a sequential therapy using clofarabine for cytoreduction followed by conditioning for haploidentical hematopoietic stem cell transplantation (HSCT) in patients with non-remission acute leukemia. Patients received clofarabine (5 × 30 mg/m(2) IV) followed by a T cell replete haploidentical transplantation for AML (n = 15) or ALL (n = 3). Conditioning consisted of fludarabine, cyclophosphamide plus either melphalan, total body irradiation or treosulfan/etoposide. High-dose cyclophosphamide was administered for post-grafting immunosuppression. Neutrophil engraftment was achieved in 83 % and complete remission in 78 % at day +30. The rate of acute graft versus host disease (GvHD) grade II-IV was 22 %, while chronic GvHD occured in five patients (28 %). Non-relapse mortality (NRM) after 1 year was 23 %. At a median follow-up of 19 months, estimated overall survival and relapse-free survival at 1 year from haploidentical HSCT were 56 and 39 %, respectively. Non-hematological regimen-related grade III-IV toxicity was observed in ten patients (56 %) and included most commonly transient elevation of liver enzymes (44 %), mucositis (40 %), and skin reactions including hand-foot syndrome (17 %), creatinine elevation (17 %), and nausea/vomiting (17 %). The concept of a sequential therapy using clofarabine for cytoreduction followed by haploidentical HSCT proved to be feasible and allows successful engraftment, while providing an acceptable toxicity profile and anti-leukemic efficacy in patients with advanced acute leukemia. NRM and rate of GvHD were comparable to results after HSCT from HLA-matched donors.Annals of Hematology 08/2013; 92(10). DOI:10.1007/s00277-013-1862-6 · 2.40 Impact Factor
Journal of Clinical Oncology 05/2013; 31(19). DOI:10.1200/JCO.2012.45.4728 · 17.88 Impact Factor