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Gender differences in doxorubicin pharmacology for subjects with chemosensitive cancers of young adulthood

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Abstract

Purpose

For many cancers, adolescents and young adults (AYA) have worse outcomes than for children and adults. Many factors may contribute to the AYA survival gap, including differences in biology, therapeutic intent, and adherence to therapy. It has been observed that male AYAs have poorer outcomes than females. The purpose of this work was to test the proposition that gender-related pharmacologic factors may account for a component of the AYA survival gap.

Patients and methods

A prospective, multi-institutional pharmacologic study of 79 patients in total with chemosensitive cancers (Ewing sarcoma, osteosarcoma and Hodgkin lymphoma) was conducted, with conventional doxorubicin treatment. Pharmacokinetic data of 13 children, 40 AYAs and 13 adults were valid for analysis. Population pharmacokinetics models were developed for doxorubicin and its metabolite doxorubicinol based on the data created in this study. Consequently, model-based analysis was conducted to investigate the relevant topics.

Results

The clearance of doxorubicinol (normalized to body surface area), the main active metabolite of doxorubicin, appears faster in male AYAs than female (p = 0.04, 95% CI 0.1–3.9 L/h). The exposure of doxorubicinol (normalized to dose) is lower in male AYA than female (p = 0.03, 95% CI − 0.005 to − 0.0002 h/L). These might be correlated to the observed difference on nadir neutrophil count between male AYA and female (p = 0.027, 95% CI 0.09–1.4).

Conclusion

Gender-related differences in doxorubicin pharmacology may account for worse outcomes for male AYAs with chemosensitive cancers compared to females. These findings may reduce the AYA survival gap compared to other age groups.

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Acknowledgements

Funding was provided by Victorian Cancer Agency (Grant no. CTPS_08_18).

Author information

Authors and Affiliations

  1. School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia

    Z. Liu & J. Martin

  2. Clinical Pharmacology and Department of Medicine, The Royal Children’s Hospital, Melbourne, Australia

    Z. Liu, N. Cranswick & M. Zacharin

  3. Division of Cancer Medicine, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Australia

    L. Orme, J. Desai, M. Michael, A. Herschtal & J. Sivasuthan

  4. Royal Children’s Hospital, Brisbane, QLD, Australia

    L. Orme

  5. University College London Hospital, London, UK

    B. Seddon

  6. Brisbane Children’s Hospital, Brisbane, QLD, Australia

    W. Nicholls

  7. Princess Alexandra Hospital, Brisbane, QLD, Australia

    W. Nicholls & D. Thomson

  8. Starship Children’s Hospital, Auckland, New Zealand

    D. Porter

  9. Children’s Hospital Westmead, Sydney, NSW, Australia

    G. McCowage

  10. Border Medical Oncology, Albury-Wodonga, VIC, Australia

    C. Underhill

  11. Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

    D. M. Thomas

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Appendices

Appendix 1

See Table 3.

Table 3 Common chemotherapy regimens used in this study
Full size table

Appendix 2

During the modelling process, the fraction (Fm, in Fig. 2) of doxorubicin metabolized to doxorubicinol was fixed as 22% [34]. The parameter value of Q4 was calculated as 22% of CLDoxo (39.0 L/h/1.8 m2 in Table 2). The reason of fixing Fm is for parameter identifiability purpose. In the model, the metabolite volume (V4) is dependent on the amount of doxorubicinol compared to the concentration of doxorubicinol and the amount of doxorubicinol is dependent on the fractional of doxorubicin drug metabolized (Fm). V4 and Fm cannot be identified simultaneously in the model.

In similar recent studies of modelling doxorubicin and its metabolite, two methods were applied to bypass the issue of parameter identifiability. One way was to fix directly the value of V4 [34], the other way was to fix Fm or Q4 [26, 29]. Of note, the sources of the fixed values of Fm or Q4 were not elucidated in Kontny and Kunarajah’s work, and the fixed values appear rather arbitrary. In our study, we fixed the value of Fm as estimated in Pérez-Blanco’s work. Consequently, the parameter values estimated in this study (i.e. CLDox’ol and V4) depend on the fixed value of Fm and are apparent values.

Worthwhile to notice that the value of Fm fixed in our study is an apparent, not absolute value. The fixed fraction Fm (no matter is 22% or other values) would not undermine our conclusion (i.e. clearance of dox’ol is faster in male AYA than female). This is because different fraction values used only change the clearance proportionally.

Appendix 3

See Figs. 13 and 14.

Fig. 13
figure 13

Prediction-corrected and variance-corrected VPCs for doxorubicin for AYA patients. The raw data are represented as black circles and lines. Grey shaded areas are the 90% confidence interval for the 5th, 50th and 95th percentiles of the simulated data. Four bins are used and the short yellow bars are the bin boundaries

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Fig. 14
figure 14

Prediction-corrected and variance-corrected VPCs for doxorubicinol for AYA patients. The raw data are represented as black circles and lines. Grey shaded areas are the 90% confidence interval for the 5th, 50th and 95th percentiles of the simulated data. Four bins are used and the short yellow bars are the bin boundaries

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Liu, Z., Martin, J., Orme, L. et al. Gender differences in doxorubicin pharmacology for subjects with chemosensitive cancers of young adulthood. Cancer Chemother Pharmacol 82, 887–898 (2018). https://doi.org/10.1007/s00280-018-3683-8

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