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Daunorubicin and Its Active Metabolite Pharmacokinetic Profiles in Acute Myeloid Leukaemia Patients: A Pharmacokinetic Ancillary Study of the BIG-1 Trial

Daunorubicin pharmacokinetics (PK) are characterised by an important inter-individual variability, which raises questions about the optimal dose regimen in patients with acute myeloid leukaemia. The aim of the study is to assess the joint daunorubicin/daunorubicinol PK profile and to define an optim...

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Main Authors: Guillaume Drevin (Author), Marie Briet (Author), Caroline Bazzoli (Author), Emmanuel Gyan (Author), Aline Schmidt (Author), Hervé Dombret (Author), Corentin Orvain (Author), Aurelien Giltat (Author), Christian Recher (Author), Norbert Ifrah (Author), Philippe Guardiola (Author), Mathilde Hunault-Berger (Author), Chadi Abbara (Author)
Format: Book
Published: MDPI AG, 2022-04-01T00:00:00Z.
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Summary:Daunorubicin pharmacokinetics (PK) are characterised by an important inter-individual variability, which raises questions about the optimal dose regimen in patients with acute myeloid leukaemia. The aim of the study is to assess the joint daunorubicin/daunorubicinol PK profile and to define an optimal population PK study design. Fourteen patients were enrolled in the PK ancillary study of the BIG-1 trial and 6-8 samples were taken up to 24 h after administration of the first dose of daunorubicin (90 mg/m<sup>2</sup>/day). Daunorubicin and daunorubicinol quantifications were assessed using a validated liquid chromatography technique coupled with a fluorescence detector method. Data were analysed using a non-compartmental approach and non-linear mixed effects modelling. Optimal sampling strategy was proposed using the R function PFIM. The median daunorubicin and daunorubicinol AUC0-tlast were 577 ng/mL·hr (Range: 375-1167) and 2200 ng/mL·hr (range: 933-4683), respectively. The median metabolic ratio was 0.32 (range: 0.1-0.44). Daunorubicin PK was best described by a three-compartment parent, two-compartment metabolite model, with a double first-order transformation of daunorubicin to metabolite. Body surface area and plasma creatinine had a significant impact on the daunorubicin and daunorubicinol PK. A practical optimal population design has been derived from this model with five sampling times per subject (0.5, 0.75, 2, 9, 24 h) and this can be used for a future population PK study.
Item Description:10.3390/pharmaceutics14040792
1999-4923

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