Monitoração terapêutica do bussulfano oral, após uso de dose teste e durante condicionamento, em pacientes submetidos a transplante alogênico de células-tronco hematopoiéticas / Therapeutic monitoring of oral busulfan, after the use of test dose and during conditioning regimen, in patients undergoing allogeneic hematopoietic stem cell transplantation

AUTOR(ES)
FONTE

IBICT - Instituto Brasileiro de Informação em Ciência e Tecnologia

DATA DE PUBLICAÇÃO

13/04/2012

RESUMO

Busulfan is an alkylating agent, used for conditioning patients undergoing hematopoietic stem cell transplantation (HSCT). It presents narrow therapeutic range and high variability in pharmacokinetics among patients and doses in the same patient. High plasma concentrations (>1000 ng mL-1) have been related to toxicity, such as sinusoidal obstruction syndrome, whereas low levels (<600 ng mL-1) have been associated with primary disease relapse or graft rejection. To avoid problems related to this treatment, therapeutic drug monitoring with dose adjustment has been proposed. Among the methods described, highperformance liquid chromatography (HPLC) is often used. This study aimed at optimizing and validating a technique to dose busulfan by HPLC coupled with photodiode array detector (PDA) and applying it to patientes undergoing HSCT in Goiás. We included eight patients in the group for therapeutic monitoring (MG) and eight in the control group (CG), i.e., with no intervention. Patients in the MG received the test dose (TD) 14 days before the treatment; after determining busulfan pharmacokinetic profile for each patient, the dose was adjusted to the therapeutic objective of 900 ng mL-1. The conditions for chromatography run were: HPLC/PDA, column ACE C18 (150 mm x 4 mm); mobile phase methanol/water/acetonitrile (65:20:15, v/v/v); eluent flow rate of 1 mL min-1; internal standard 1,6-bis-(methanesulfonyloxy)hexane; UV detection λ = 276 nm; derivatization with sodium diethylcarbamate; liquid-liquid extraction with ethyl acetate after precipitation with acetonitrile. We included eight patients in the group for therapeutic monitoring (MG) and eight in the control group (CG). Results obtained: linearity, analyzed through the calibration curve, of 2005000 ng mL-1; precision, in terms of repeatability (intra-run), of 1.25%-11.25%, and intermediary (inter-run), of 2.17%-10.71%; accuracy of 89.61%-102.18%; recovery of 89%. Half of the patients required dose increase and the mean dose administered was 1.020.19 mg kg-1. High variability was observed in assessed pharmacokinetic parameters: 38% variation in Css ____ between TD and conditioning regimen; half-life increased by 11%; ClT/F decreased by 30%, suggesting accumulation of busulfan when the drug is administered in a multiple dose regimen. Although lower than reported in the literature, this variation may be associated with toxicity or failure in treatment, justifying patient monitoring and enhancing validity of previous pharmacokinetic evaluation using TD regimen. Compared to the CG, this variation did not present impact on toxicity, mortality, and survival rates. Other studies with intervention during monitoring and a higher number of patients may present positive impact on the results of HSCT.

ASSUNTO(S)

bussulfano transplante de células-tronco hematopoiéticas cromatografia líquida farmacocinética clinica medica busulfan liquid chromatography hematopoietic stem cell transplantation pharmacokinetics

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