title: Influence of fludarabine on the pharmacokinetics of oral busulfan during pretransplant conditioning for hematopoietic stem cell transplantation.
abstract: This study evaluated the influence of fludarabine on the pharmacokinetics of busulfan administered orally to patients receiving a conditioning regimen for hematopoietic allogeneic stem cell transplantation (HSCT). Twenty-six patients treated with oral busulfan (1 mg/kg/6 h for 4 days) were divided into two groups according to the concomitant administration of fludarabine (n = 11; 30 mg/m(2) for 5 days) or subsequent administration of cyclophosphamide (n = 15; 60 mg/kg for 2 days). Serial blood samples were collected on Day 4 of busulfan administration. Plasma busulfan concentrations were determined by HPLC-UV and the pharmacokinetic parameters were calculated using the WinNonlin program. Patients concomitantly treated with fludarabine showed reduced apparent clearance of busulfan (110.5 mL/h/kg vs. 157.4 mL/h/kg) and higher AUC0-6 (area under the plasma concentrations vs. time curve) than patients subsequently treated with cyclophosphamide (7.9 µg h/mL vs. 5.7 µg h/mL). No association was observed between busulfan AUC0-6 and clinical evolution of the patients. Although plasma busulfan concentrations were higher in patients receiving concomitant fludarabine, myelosuppression-related toxicity was less frequent than in patients treated with busulfan and cyclophosphamide. The results suggest that patients treated with fludarabine should receive 30% lower busulfan doses during conditioning protocols for HSCT.
authors: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
authors: Francine Attié
authors: FA
authors: de Castro
authors: Vera Lucia
authors: VL
authors: Lanchote
authors: Julio Cesar
authors: JC
authors: Voltarelli
authors: Virgílio Antônio Rensi
authors: VA
authors: Colturato
authors: Belinda Pinto
authors: BP
authors: Simões
mesh_terms: D000293:Adolescent; D000328:Adult; D000477:Alkylating Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002066:Busulfan / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004347:Drug Interactions; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000008:administration & dosage*; D019172:Transplantation Conditioning; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D055815:Young Adult
chemical_list: D000477:Alkylating Agents; D019653:Myeloablative Agonists; D003520:Cyclophosphamide; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine
keywords: busulfan; fludarabine; hematopoietic stem cell transplantation; pharmacokinetics