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Pharmacokinetics and individualized dose adjustment of intravenous busulfan in children with advanced hematologic malignancies undergoing allogeneic stem cell transplantation.
Biol Blood Marrow Transplant. 2004 Nov; 10(11):805-12.BB

Abstract

We investigated the pharmacokinetics (PK) of a recently approved intravenous busulfan (IVBU) formulation as a part of the preparative regimen in 20 children with advanced hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation. Seventeen patients received a thiotepa, IVBU, and cyclophosphamide-based regimen, and 3 patients received an IVBU and cyclophosphamide-based regimen. All patients received IVBU 0.8 mg/kg for the first 2 doses; thereafter, the IVBU dose was modified, if required, to achieve a final area under the concentration-time curve (AUC) at steady state of 1150 micromol/L/min per dose (range, 1000-1300 micromol/L/min per dose; SD +/-13%) based on the first-dose PK determination. PK studies were repeated on subsequent doses to verify the final AUC. Initial mean IVBU clearance and half-life were 3.96 mL/min/kg and 1.98 hours, respectively. Sixteen (80%) of the 20 patients received dose adjustments: 14 patients required dose escalations, and 2 required dose reductions. Overall, thirteen (72%) of 18 available sample sets at final follow-up PK analysis showed the IVBU exposure to be within the targeted range. IVBU PK was linear, and interpatient variability was much lower than that observed with oral busulfan. IVBU was well tolerated, and no case of hepatic veno-occlusive disease was encountered. Mild and transient hyperbilirubinemia was observed in 7 patients. Thirteen of the 20 patients were alive at a median follow-up of 651 days (range, 386-1555 days). We conclude that a standardized IVBU dose of 0.8 mg/kg in children does not always result in an AUC within the reference range defined in this study. Therapeutic drug monitoring with dose adjustment based on first-dose PK can optimize the systemic busulfan exposure for children undergoing allogeneic hematopoietic stem cell transplantation.

Authors+Show Affiliations

Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. htran@mdanderson.orgNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15505611

Citation

Tran, Hai, et al. "Pharmacokinetics and Individualized Dose Adjustment of Intravenous Busulfan in Children With Advanced Hematologic Malignancies Undergoing Allogeneic Stem Cell Transplantation." Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, vol. 10, no. 11, 2004, pp. 805-12.
Tran H, Petropoulos D, Worth L, et al. Pharmacokinetics and individualized dose adjustment of intravenous busulfan in children with advanced hematologic malignancies undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2004;10(11):805-12.
Tran, H., Petropoulos, D., Worth, L., Mullen, C. A., Madden, T., Andersson, B., Choroszy, M., Nguyen, J., Webb, S. K., & Chan, K. W. (2004). Pharmacokinetics and individualized dose adjustment of intravenous busulfan in children with advanced hematologic malignancies undergoing allogeneic stem cell transplantation. Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, 10(11), 805-12.
Tran H, et al. Pharmacokinetics and Individualized Dose Adjustment of Intravenous Busulfan in Children With Advanced Hematologic Malignancies Undergoing Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2004;10(11):805-12. PubMed PMID: 15505611.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetics and individualized dose adjustment of intravenous busulfan in children with advanced hematologic malignancies undergoing allogeneic stem cell transplantation. AU - Tran,Hai, AU - Petropoulos,Demetrios, AU - Worth,Laura, AU - Mullen,Craig A, AU - Madden,Timothy, AU - Andersson,Borje, AU - Choroszy,Mary, AU - Nguyen,John, AU - Webb,Susannah K, AU - Chan,Ka Wah, PY - 2004/10/27/pubmed PY - 2005/4/1/medline PY - 2004/10/27/entrez SP - 805 EP - 12 JF - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation JO - Biol Blood Marrow Transplant VL - 10 IS - 11 N2 - We investigated the pharmacokinetics (PK) of a recently approved intravenous busulfan (IVBU) formulation as a part of the preparative regimen in 20 children with advanced hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation. Seventeen patients received a thiotepa, IVBU, and cyclophosphamide-based regimen, and 3 patients received an IVBU and cyclophosphamide-based regimen. All patients received IVBU 0.8 mg/kg for the first 2 doses; thereafter, the IVBU dose was modified, if required, to achieve a final area under the concentration-time curve (AUC) at steady state of 1150 micromol/L/min per dose (range, 1000-1300 micromol/L/min per dose; SD +/-13%) based on the first-dose PK determination. PK studies were repeated on subsequent doses to verify the final AUC. Initial mean IVBU clearance and half-life were 3.96 mL/min/kg and 1.98 hours, respectively. Sixteen (80%) of the 20 patients received dose adjustments: 14 patients required dose escalations, and 2 required dose reductions. Overall, thirteen (72%) of 18 available sample sets at final follow-up PK analysis showed the IVBU exposure to be within the targeted range. IVBU PK was linear, and interpatient variability was much lower than that observed with oral busulfan. IVBU was well tolerated, and no case of hepatic veno-occlusive disease was encountered. Mild and transient hyperbilirubinemia was observed in 7 patients. Thirteen of the 20 patients were alive at a median follow-up of 651 days (range, 386-1555 days). We conclude that a standardized IVBU dose of 0.8 mg/kg in children does not always result in an AUC within the reference range defined in this study. Therapeutic drug monitoring with dose adjustment based on first-dose PK can optimize the systemic busulfan exposure for children undergoing allogeneic hematopoietic stem cell transplantation. SN - 1083-8791 UR - https://www.unboundmedicine.com/medline/citation/15505611/Pharmacokinetics_and_individualized_dose_adjustment_of_intravenous_busulfan_in_children_with_advanced_hematologic_malignancies_undergoing_allogeneic_stem_cell_transplantation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1083879104004252 DB - PRIME DP - Unbound Medicine ER -