Monitoração terapêutica do bussulfano oral, após uso de dose teste e durante condicionamento, em pacientes submetidos a transplante alogênico de células-tronco hematopoiéticas
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Data
2012-04-13
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Universidade Federal de Goiás
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 200 5000 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 1.02±0.19 mg kg-1. High variability was
observed in assessed pharmacokinetic parameters: 38% variation in
Css
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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.
Descrição
Citação
EFFTING, Cristiane. Therapeutic monitoring of oral busulfan, after the use of test dose and during conditioning regimen, in patients undergoing allogeneic hematopoietic stem cell transplantation. 2012. 181 f. Tese (Doutorado em Ciencias da Saude) - Universidade Federal de Goiás, Goiânia, 2012.