Single-nucleotide variants linked to doxorubicin pharmacokinetics

Several factors are directly associated with either an increase or a decrease of pharmacokinetic parameters of doxorubicin, reports a recent study.

Furthermore, decreased clearance, volume of distribution in the peripheral compartment (V2), and increased area under the curve are associated with systolic dysfunction, while decreased intercompartmental clearance (Q) and V2 correlate with diastolic dysfunction.

The researchers included 70 paediatric patients treated with doxorubicin, in whom 189 biological samples were obtained to determine doxorubicin concentrations (1 to 3 samples per patient) at different times for 20 hours.

Low body mass index and age ≤7 years contributed to a decreased clearance of doxorubicin and female gender to increased clearance of doxorubicin. Low body mass index and low height correlated with a decrease and an increase in the Q of doxorubicin, respectively.

Moreover, TT homozygosity of the single-nucleotide variant rs3743527 of the ABCC1 gene correlated with an increase in clearance and a decreased area under the curve, AA homozygosity of the single-nucleotide variant rs1883112 of the NCF4 gene with a decrease in V2, and GG homozygosity of CBR3 rs1056892 with increasing area under the curve.

“These results may contribute to the effective and safe use of doxorubicin in paediatric patients with leukaemia,” the researchers said.

“Doxorubicin is an important antineoplastic agent with wide interindividual variability in response to treatment and in its cardiotoxic effects,” according to the researchers.