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Doctoral Thesis
DOI
https://doi.org/10.11606/T.60.2019.tde-23052019-103234
Document
Author
Full name
Milena Locci de Oliveira
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2019
Supervisor
Committee
Lanchote, Vera Lucia (President)
Pereira, Leonardo Régis Leira
Fernandes, Bruno José Dumêt
Gaitani, Cristiane Masetto de
Pontes, Lorena Lôbo de Figueiredo
Title in Portuguese
Esquema de amostragem esparsa para avaliar a farmacocinética da daunorrubicina e seu metabólito daunorrubicinol em pacientes adultos e pediátricos diagnosticados com leucemia mieloide aguda
Keywords in Portuguese
Amostragem esparsa
Daunorrubicina
Farmacocinética
Leucemia
Metabolismo
Abstract in Portuguese
O objetivo principal do estudo foi estabelecer um esquema de amostragem esparsa para propiciar a avaliação da farmacocinética da daunorrubicina (DAUN) e seu metabólito daunorrubicinol (DAUNOL) em grande número de pacientes adultos e pediátricos. Foram investigados pacientes adultos (> 12 anos; n=12) diagnosticados com leucemia mieloide aguda (LMA) com indicação para uso da DAUN (60 mg/m2/dia) por infusão intravenosa de 1 h durante 3 dias consecutivos. As coletas seriadas de sangue e urina foram realizadas ao longo das 3 infusões, ocorrendo até 144 h após o início da primeira infusão. Os métodos de análise sequencial da DAUN e DAUNOL em plasma, ultrafiltrado de plasma e urina empregando LC-MS/MS foram validados nos intervalos de 0,1 a 1000 ng/mL de plasma, 0,05 a 40 ng/mL de ultrafiltrado e de 0,5 a 3000 ng/mL de urina. A farmacocinética da DAUN e DAUNOL, avaliada por modelo bicompartimental e monocompartimental, mostrou meias-vidas de eliminação de 8,7 (7,98-9,48) e 15,04 (13,92-16,26) h, respectivamente. A razão metabólica de AUC0-? DAUNOL/DAUN foi de 6,25, variando individualmente entre 4,16 a 8,79, um dado que exibe variação interindividual de aproximadamente 100%. O clearance total da DAUN foi de 289,54 (254,20-329,54) L/h, o clearance renal de 12,66 (10,79-14,87) L/h e o clearance hepático de 274,81 (236,30-319,60) L/h. O clearance de formação do metabólito DAUNOL foi de 22,78 (18,20-28,50) L/h. A ligação da DAUN às proteínas plasmáticas foi de 72,41 (67,02-78,24) % e do DAUNOL de 69,88 (66,72-73,20) %. Os pacientes genotipados com a variante rs25678 (C>G) da CBR1 (GG e CG; n=11) apresentaram tendência de maiores valores de AUC da DAUN quando comparados ao paciente genotipado como CC (n=1). O paciente genotipado com a variante rs1695 da GSTP1 (Ile105Val) (GG; n=1) também apresentou tendência de maior valor de AUC da DAUN quando comparado aos pacientes genotipados como AG ou AA (n=11). O modelo de farmacocinética populacional da DAUN e DAUNOL, desenvolvido com dados de pacientes pediátricos virtuais (n=12), estruturado com cinco compartimentos e validado com métodos gráficos e estatísticos, apresentou bom desempenho preditivo e mostrou-se adequado para fins de simulação de dados. A estratégia de amostragem esparsa (n=3) com tempos de coleta entre 36-85 h após o início da primeira infusão permitiu estimar os parâmetros farmacocinéticos individuais da DAUN e DAUNOL de forma tão robusta quanto a estratégia de amostragem com coletas seriadas, oferecendo uma ferramenta viável a ser agregada em futuros estudos multicêntricos empenhados na predição da dose não empírica de DAUN em pacientes adultos e pediátricos
Title in English
Sparse sampling scheme to evaluate the pharmacokinetics of daunorubicin and its metabolite daunorubicinol in adult and pediatric patients diagnosed with acute myeloid leukemia
Keywords in English
Daunorubicin
Leukemia
Metabolism
Pharmacokinetics
Sparse sampling
Abstract in English
The main objective of the study was to establish a sparse sampling scheme to assess the pharmacokinetics of daunorubicin (DAUN) and its metabolite daunorubicinol (DAUNOL) in a large number of adult and pediatric patients. There were investigated adult patients (> 18 years; n = 12) diagnosed with acute myeloid leukemia (AML) with indication for use of DAUN (60 mg/m2/day) by intravenous infusion of 1 h for 3 consecutive days. Serial blood and urine samples were collected throughout the 3 infusions, up to 144 h after the start of the first infusion. Sequential DAUN and DAUNOL analysis methods in plasma, plasma ultrafiltrate and urine by LC-MS/MS were validated at intervals of 0.1 to 1000 ng/mL plasma, 0.05 to 40 ng/mL ultrafiltrate and of 0.5 to 3000 ng/ml urine. The pharmacokinetics of DAUN and DAUNOL, evaluated by a bicompartmental and monocompartmental model, showed elimination half-lives of 8.7 (7.98-9.48) and 15.04 (13.92-16.26) h, respectively. The metabolic ratio of AUC0-? DAUNOL/DAUN was 6.25, ranging from 4.16 to 8.79, individually, presenting an interindividual variation of approximately 100%. Total DAUN clearance was 289.54 (254.20-329.54) L/h, renal clearance was 12.66 (10.79-14.87) L/h and hepatic clearance was 274.81 (236 , 30-319.60) L/hr. The metabolite DAUNOL formation clearance was 22.78 (18.20-28.50) L/h. The DAUN binding to plasma proteins was 72.41 (67.02-78.24)% and DAUNOL 69.88 (66.72-73.20)%. Patients genotyped with the rs25678 (C> G) variant of CBR1 (GG and CG; n = 11) showed a tendency for higher DAUC AUC values when compared to the genotyped patient as CC (n = 1). The genotyped patient with the rs1695 variant of GSTP1 (Ile105Val) (GG; n = 1) also showed a higher AUC value of DAUN when compared to genotyped patients such as AG or AA (n = 11). The population pharmacokinetic model of DAUN and DAUNOL, developed with data from virtual pediatric patients (n = 12), structured with five compartments and validated with graphical and statistical methods, presented good predictive performance and was adequate for data simulation purposes. The sampling strategy (n = 3) with collection times between 36-85 h after the start of the first infusion allowed the estimation of DAUN and DAUNOL individual pharmacokinetic parameters as robust as the sampling strategy with serial collections, a feasible tool to be aggregated in future multicenter studies aimed at predicting the non-empirical dose of DAUN in adult and pediatric patients
 
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Release Date
2021-05-22
Publishing Date
2019-11-22
 
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