Pharmacokinetic targeting of i.v. BU with fludarabine as conditioning before hematopoietic cell transplant: the effect of first-dose area under the concentration time curve on transplant-related outcomes

• Published in: Bone marrow transplantation (Basingstoke) Vol. 46; no. 11; pp. 1418 - 1425
• Main Authors: PERKINS, J, FIELD, T, MILONE, M. C, GARDINER, J. A, MILLER, S, ANASETTI, C, KIM, J, KHARFAN-DABAJA, M. A, AYALA, E, PEREZ, L, FERNANDEZ, H, FANCHER, K, TATE, C, SHAW, L. M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.11.2011
• Subjects: Adult; Aged; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Area Under Curve; Biological and medical sciences; Bone marrow; Bone marrow, stem cells transplantation. Graft versus host reaction; Busulfan; Busulfan - administration & dosage; Busulfan - pharmacokinetics; Concentration time; Disease-Free Survival; Dosage; Dosage and administration; Drug targeting; Female; Fludarabine; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic stem cells; Humans; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - therapy; Male; Medical sciences; Middle Aged; Minority & ethnic groups; Myeloablative Agonists - administration & dosage; Myeloablative Agonists - pharmacokinetics; Pharmacokinetics; Pharmacology; Recurrence; Retrospective Studies; Stem cell transplantation; Toxicity; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplantation; Transplantation Conditioning - methods; Transplants & implants; Vidarabine - administration & dosage; Vidarabine - analogs & derivatives; Antineoplastic agent; Purine nucleotide; Prognosis; Targeting; Hematology; Hematopoietic cell; Nucleotide analog; hematopoietic cell transplant; Fludarabine; BU; Antimetabolic; Area under the curve; Fluorine Organic compounds; Conditioning; Pharmacokinetics; Dose
• ISSN: 0268-3369; 1476-5365
• DOI: 10.1038/bmt.2010.315

We used pharmacokinetic (PK) targeting of BU in 145 consecutive patients treated with fludarabine and i.v. BU. BU was given once daily at 130 mg/m(2) per day on days 1 and 2; doses for days 3 and 4 were adjusted in 92 patients (63%) to an average daily area under the concentration-time curve (AUC) of 5300 μM/min. In the remaining 53 patients, the first-dose AUC was within the target range and no dosing adjustments were required. First-dose AUC, maximum concentration and clearance were not correlated with age, race, ethnicity, performance status, or hematopoietic cell transplant comorbidity index. Women had higher clearance than men (median 2.9 vs 2.5 mL/min/kg; P=0.001). BU toxicities were not associated with first-dose AUC or any other PK parameter measured. First-dose BU AUC was not associated with non-relapse mortality (NRM) or survival, but higher AUC was predictive of relapse. We did not find an increased risk of toxicity or NRM in patients with high first-dose AUC presumably because of the dose adjustment. We conclude that PK targeting of BU as described here provides a simple, safe and effective method of delivering high BU doses before transplantation in a wide variety of patients.