Impact of single nucleotide variants and nutritional status on
population pharmacokinetics of Doxorubicin, and its effect on
cardiotoxicity in children with leukemia.
Doxorubicin (DOX) is a highly useful antineoplastic in the treatment of
different types of cancer; however, its use is limited due to its wide
variability between patients in their susceptibility to the cardiotoxic
effects of anthracyclines. Purpose: The aim of this study was
to determine the effect of single nucleotide variants (SNV) and the
nutritional status on the population pharmacokinetics of DOX, and their
repercussions on cardiotoxicity in pediatric patients with leukemia.
Patients and methods: Seventy pediatric patients treated with
DOX were studied, in whom 189 biological samples (1 to 3 samples per
patient) were obtained at different random times, for 20 hours.
Results: Body mass index, age ≤ 7 years and female sex were
associated with a decrease in DOX clearance. Low height was associated
with an increase in pharmacokinetics parameters of DOX. The Wild type
(WT) genotype of ABCC1 rs3743527 variant was associated with an
increase in clearance (CL), and the homozygous variant (HV) genotype of
NCF4 rs1883112 SNV was associated with a decrease in peripheral
compartment (V2) of the peripheral compartment. Conclusion: The
SNV of the ABCC1 and NCF4 genes influence the increase and
decrease in DOX CL, in addition, characteristics such as sex and height
were associated with the decrease and increase in DOX CL respectively.
The pharmacokinetic parameters show an influence on the development of
cardiotoxicity by DOX. The decrease in CL and V2 were associated with
systolic disfunction. The decrease in the intercompartmental clearance
(Q) and in the volume distribution (V2) were associated with diastolic
disfunction. In clinical practice, these results may contribute to the
effective and safe use of DOX in pediatric cancer patients.