title: Individualizing oral busulfan dose after using a test dose in patients undergoing hematopoietic stem cell transplantation: pharmacokinetic characterization.
abstract: BACKGROUND
  Busulfan is an alkylating agent used for conditioning patients undergoing hematopoietic stem cell transplantation with a narrow therapeutic range and highly variable pharmacokinetics. High concentrations induce toxicity, especially hepatic veno-occlusive disease, also referred to as sinusoidal obstruction syndrome. This study aimed to assess busulfan pharmacokinetic variability in pretransplant conditioning regimens using an analytical method validated by high-performance liquid chromatography coupled to diode array detector (HPLC/PDA).
  
  
  METHODS
  Eight patients who used the test dose (TD) of 1 mg/kg busulfan 10 days before conditioning were included, and 10 serial blood samples were collected to determine: the elimination half-life (t1/2), total area under the curve (AUCT), total clearance (Cl(T)/F), and plasma concentration at steady state (C(ss)), using a monocompartmental model and first-order kinetics. The instrumental conditions were: HPLC/PDA Shimadzu, column ACE C18 (150 mm × 4 mm); methanol/water/acetonitrile (65:20:15) eluent flow rate of 1 mL/min; 1,6-bis-(methanesulfonyloxy)-hexane; UV λ = 276 nm; analysis time 17 minutes; and derivatization with sodium diethylcarbamate. The dose was adjusted, and 4 blood samples per day were collected at days 2, 3, and 4 of treatment for new plasma determinations.
  
  
  RESULTS
  Four patients needed higher doses; the mean dose administered was 1.02 ± 0.19 mg/kg. Mean results at TD: t1/2 = 2.88 ± 0.5 hours; Cl(T)/F = 0.18 ± 0.03 L · h(-1) · kg(-1); AUC(T) = 5461.00 ± 961.15 ng · mL(-1) · h(-1); and C(ss) = 911.3 ± 159.8 ng/mL. Mean results of samples collected during conditioning: t1/2 = 3.21 ± 0.9 hours; Cl(T)/F = 0.13 ± 0.02 L · h(-1) · kg(-1); AUC(T) = 7571 ± 1705 ng · mL(-1) · h(-1); and C(ss) = 1262.0 ± 284.3 ng/mL.
  
  
  CONCLUSIONS
  High variability in the assessed pharmacokinetic parameters was observed, with a 38% variation in C(ss) between TD and conditioning regimen; Cl(T)/F decreased by 30%, suggesting drug accumulation after multiple-dose regimen. Although being lower than reported in the literature, this variation may be associated with toxicity of the proposed treatment, justifying patient monitoring and enhancing validity of previous pharmacokinetic evaluation using TD regimen.
authors.affiliation: *Núcleo de Estudos e Pesquisas Tóxico-Farmacológicas, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia; †Departamento de Farmácia, Universidade Estadual de Goiás, Anápolis; and ‡Unidade de Transplante de Medula Óssea do Hospital Araújo Jorge, Goiânia, Brazil.
authors.forename: Cristiane
authors.initials: C
authors.lastname: Effting
authors.forename: Adriano
authors.initials: A
authors.lastname: de Moraes Arantes
authors.forename: Luciana V
authors.initials: LV
authors.lastname: Queiroz Labre
authors.forename: Wilsione J
authors.initials: WJ
authors.lastname: Carneiro
authors.forename: Jerônimo R
authors.initials: JR
authors.lastname: de Oliveira Neto
authors.forename: César
authors.initials: C
authors.lastname: Bariani
authors.forename: Caroline R
authors.initials: CR
authors.lastname: Rodrigues
authors.forename: Andryne R
authors.initials: AR
authors.lastname: Rodrigues
authors.forename: Luiz C
authors.initials: LC
authors.lastname: Cunha
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002066:Busulfan / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006207:Half-Life; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007202:Indicators and Reagents; D007938:Leukemia / Q000378:metabolism / Q000628:therapy; D008297:Male; D008875:Middle Aged; D057285:Precision Medicine; D011446:Prospective Studies; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D007202:Indicators and Reagents; D002066:Busulfan