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Slower degradation rate of cytarabine in blood samples from acute myeloid leukemia by comparison with control samples

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Abstract

Purpose

Cytarabine, a key chemotherapy agent for acute myeloid leukemia (AML) treatment, is deaminated into inactive uracil-arabinoside by cytidine deaminase. This deamination leads to samples stability issues with respect to clinical pharmacokinetic trials. The aim of our study was to study in vitro cytarabine stability in blood samples obtained from AML patients.

Methods

Cytarabine quantification was performed using a fully validated LC/MS/MS method. In vitro cytarabine stability was assessed at room temperature over 24 h in samples coming from 14 AML patients and 7 control patients (CTRL) with no hematological malignancy. In vitro concentrations versus time data were analyzed using a noncompartmental approach.

Results

Cytarabine in vitro area under the curve (AUCIVlast) was 22-fold higher in AML samples as compared to CTRL samples (AML mean (standard deviation (SD)), 51,829 (27,004) h ng/mL; CTRL mean (SD), 2356 (1250) h ng/mL, p = 0.00019). This increase was associated with a prolonged in vitro degradation half-life (t1/2IVdeg AML mean (SD), 15 (11.8) h; CTRL mean (SD), 0.36 (0.37) h, p = 0.0033). Multiple linear regression analysis showed that AML diagnosis significantly influenced t1/2IVdeg and AUCIVlas relationship.

Conclusion

Cytarabine stability is higher in AML than in CTRL samples. The absence of correlation between t1/2IVdeg and AUCIVlast in AML samples suggests that in vitro cytarabine degradation in AML is complex. These results open perspectives including the evaluation of the clinical relevance and the involved molecular mechanisms.

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Acknowledgements

We thank Angers University Hospital (Appel d’Offre Interne). We are very grateful to the principal investigators of BIG-1 trial, Prof. Dombret and Prof. Ifrah for their support.

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Authors and Affiliations

  1. Service de Pharmacologie-Toxicologie et Pharmacovigilance, Centre Hospitalo-Universitaire d’Angers, Angers, France

    Chadi Abbara, Guillaume Drevin, Séverine Férec, Sarah Ghamrawi & Marie Briet

  2. Université d’Angers, Angers, France

    Guillaume Drevin, Jean-Baptiste Robin, Aline Schmidt, Mathilde Hunault-Berger, Philippe Guardiola & Marie Briet

  3. Service de Génomique Onco-Hématologique, Centre Hospitalo-Universitaire, Angers, France

    Simon Souchet & Philippe Guardiola

  4. Service des Maladies du Sang, Centre Hospitalo-Universitaire, Angers, France

    Aline Schmidt & Mathilde Hunault-Berger

  5. Inserm, CRCINA, Angers, France

    Aline Schmidt & Mathilde Hunault-Berger

  6. Fédération Hospitalo-Universitaire GOAL, Angers, France

    Aline Schmidt, Mathilde Hunault-Berger & Marie Briet

  7. Laboratoire MitoVasc, UMR CNRS 6214 INSERM 1083, Angers, France

    Marie Briet

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  1. Chadi Abbara
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  2. Guillaume Drevin
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  3. Séverine Férec
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  7. Aline Schmidt
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  8. Mathilde Hunault-Berger
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  9. Philippe Guardiola
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Correspondence to Chadi Abbara.

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Abbara, C., Drevin, G., Férec, S. et al. Slower degradation rate of cytarabine in blood samples from acute myeloid leukemia by comparison with control samples. Cancer Chemother Pharmacol 86, 687–691 (2020). https://doi.org/10.1007/s00280-020-04150-9

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  • DOI: https://doi.org/10.1007/s00280-020-04150-9

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