TY - JOUR
T1 - Impact of single-nucleotide variants and nutritional status on population pharmacokinetics of Doxorubicin, and its effect on cardiotoxicity in children with leukemia
AU - Gándara-Mireles, Jesús Alonso
AU - Lares-Asseff, Ismael
AU - Reyes Espinoza, Elio Aarón
AU - Fierro, Ignacio Villanueva
AU - Castañeda, Verónica Loera
AU - Cordova Hurtado, Lourdes Patricia
AU - González, Carla Díaz
AU - Romero, Leslie Patrón
AU - Reyes, Horacio Almanza
N1 - Publisher Copyright:
© The Author(s) 2022.
PY - 2023/9
Y1 - 2023/9
N2 - Purpose: Doxorubicin is an important antineoplastic agent with wide interindividual variability in response to treatment and in its cardiotoxic effects. To determine the effect of genotypic status of three single-nucleotide variants in ABCC1, NCF4, and CBR3 genes and nutritional status assessed by body mass index, on the population pharmacokinetics of Doxorubicin and its cardiotoxic effects in pediatric patients with leukemia. Patients and methods: Seventy pediatric patients treated with Doxorubicin were studied, in which 189 biological samples were obtained to determine Doxorubicin concentrations (1 to 3 samples per patient) at different times, for 20 h. Results: Low body mass index and age ≤ 7 years were associated with decreased clearance of Doxorubicin, and female gender was associated with increased clearance of Doxorubicin. Low BMI and low height were associated with a decrease and increase, respectively, in the intercompartmental clearance (Q) of Doxorubicin. TT homozygosity of the single-nucleotide variant rs3743527 of the ABCC1 gene was associated with an increase in clearance and decreased area under the curve, AA homozygosity of the single-nucleotide variant rs1883112 of the NCF4 gene was associated with a decrease in the volume of distribution in the peripheral compartment (V2), and GG homozygosity of CBR3 rs1056892 with increasing area under the curve. Conclusion: Some covariates studied are directly related to the increase or decrease of the pharmacokinetic parameters of Doxorubicin. Decreased clearance, V2, and increased area under the curve were associated with systolic dysfunction, and decreased Q and V2 were associated with diastolic dysfunction. These results may contribute to the effective and safe use of Doxorubicin in pediatric patients with leukemia.
AB - Purpose: Doxorubicin is an important antineoplastic agent with wide interindividual variability in response to treatment and in its cardiotoxic effects. To determine the effect of genotypic status of three single-nucleotide variants in ABCC1, NCF4, and CBR3 genes and nutritional status assessed by body mass index, on the population pharmacokinetics of Doxorubicin and its cardiotoxic effects in pediatric patients with leukemia. Patients and methods: Seventy pediatric patients treated with Doxorubicin were studied, in which 189 biological samples were obtained to determine Doxorubicin concentrations (1 to 3 samples per patient) at different times, for 20 h. Results: Low body mass index and age ≤ 7 years were associated with decreased clearance of Doxorubicin, and female gender was associated with increased clearance of Doxorubicin. Low BMI and low height were associated with a decrease and increase, respectively, in the intercompartmental clearance (Q) of Doxorubicin. TT homozygosity of the single-nucleotide variant rs3743527 of the ABCC1 gene was associated with an increase in clearance and decreased area under the curve, AA homozygosity of the single-nucleotide variant rs1883112 of the NCF4 gene was associated with a decrease in the volume of distribution in the peripheral compartment (V2), and GG homozygosity of CBR3 rs1056892 with increasing area under the curve. Conclusion: Some covariates studied are directly related to the increase or decrease of the pharmacokinetic parameters of Doxorubicin. Decreased clearance, V2, and increased area under the curve were associated with systolic dysfunction, and decreased Q and V2 were associated with diastolic dysfunction. These results may contribute to the effective and safe use of Doxorubicin in pediatric patients with leukemia.
KW - Doxorubicin
KW - cardiotoxicity
KW - leukemia
KW - nutritional status
KW - pharmacokinetics
KW - population pharmacokinetic
KW - single-nucleotide variant
UR - http://www.scopus.com/inward/record.url?scp=85138251395&partnerID=8YFLogxK
U2 - 10.1177/10781552221117810
DO - 10.1177/10781552221117810
M3 - Artículo
C2 - 36113156
AN - SCOPUS:85138251395
SN - 1078-1552
VL - 29
SP - 1290
EP - 1305
JO - Journal of Oncology Pharmacy Practice
JF - Journal of Oncology Pharmacy Practice
IS - 6
ER -