European journal of pharmacology · 2026
Population pharmacokinetic modeling of idarubicin and idarubicinol in Acute Myeloid Leukemia induction therapy: An Ancillary Study of the BIG-1 Trial.
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Maisonneuve Stanislas, Hunault-Berger Mathilde, Drevin Guillaume, Orvain Corentin, Schmidt Aline, Giltat Aurélien, Thepot Sylvain, Briet Marie, Abbara Chadi
Аннотация
BACKGROUND: Idarubicin, a key anthracycline used in the induction treatment of acute myeloid leukemia (AML), is characterized by large interindividual pharmacokinetic (PK) variability. This variability may impact both efficacy and toxicity, highlighting the need for a better understanding of exposure variability and its determinants.
METHODS: A joint population PK model of idarubicin and its active metabolite idarubicinol was developed using data from 27 patients enrolled in the BIG-1 study. Plasma concentrations were measured on day 1 of induction therapy following intravenous idarubicin administration. Idarubicin and idarubicinol were quantified using high-performance liquid chromatography coupled with fluorescence detection. Nonlinear mixed-effects modeling was used to describe concentration-time profiles and explore associations with clinical and biological covariates.
RESULTS: Among the structures evaluated, a three-compartment model for idarubicin coupled with a two-compartment model for idarubicinol provided the best fit to the observed concentration-time data within 24 hours following infusion. Body surface area and baseline lymphocyte count were identified as exploratory covariates associated with peripheral distribution volumes.
CONCLUSIONS: This study describes idarubicin and idarubicinol concentration-time profiles over the observed 24-hour period in patients receiving AML induction therapy. Associations with body surface area and lymphocyte count require confirmation in an independent population. These findings provide a pharmacometric basis for future exposure-response investigations and prospective evaluation of model-informed therapeutic strategies approaches in AML.
METHODS: A joint population PK model of idarubicin and its active metabolite idarubicinol was developed using data from 27 patients enrolled in the BIG-1 study. Plasma concentrations were measured on day 1 of induction therapy following intravenous idarubicin administration. Idarubicin and idarubicinol were quantified using high-performance liquid chromatography coupled with fluorescence detection. Nonlinear mixed-effects modeling was used to describe concentration-time profiles and explore associations with clinical and biological covariates.
RESULTS: Among the structures evaluated, a three-compartment model for idarubicin coupled with a two-compartment model for idarubicinol provided the best fit to the observed concentration-time data within 24 hours following infusion. Body surface area and baseline lymphocyte count were identified as exploratory covariates associated with peripheral distribution volumes.
CONCLUSIONS: This study describes idarubicin and idarubicinol concentration-time profiles over the observed 24-hour period in patients receiving AML induction therapy. Associations with body surface area and lymphocyte count require confirmation in an independent population. These findings provide a pharmacometric basis for future exposure-response investigations and prospective evaluation of model-informed therapeutic strategies approaches in AML.