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

• Published in: Cancer chemotherapy and pharmacology Vol. 82; no. 5; pp. 887 - 898
• Main Authors: Liu, Z., Martin, J., Orme, L., Seddon, B., Desai, J., Nicholls, W., Thomson, D., Porter, D., McCowage, G., Underhill, C., Cranswick, N., Michael, M., Zacharin, M., Herschtal, A., Sivasuthan, J., Thomas, D. M.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2018; Springer Nature B.V
• Subjects: Adolescent; Adolescents; Adult; Age Factors; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - pharmacokinetics; Antibiotics, Antineoplastic - therapeutic use; Bone Neoplasms - drug therapy; Bone Neoplasms - metabolism; Cancer Research; Children; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - analogs & derivatives; Doxorubicin - pharmacokinetics; Doxorubicin - therapeutic use; Ewing's sarcoma; Ewings sarcoma; Female; Females; Gender; Hodgkin Disease - drug therapy; Hodgkin Disease - metabolism; Hodgkin's lymphoma; Humans; Lymphoma; Medicine; Medicine & Public Health; Models, Biological; Neoplasms - drug therapy; Neoplasms - metabolism; Oncology; Original Article; Osteosarcoma; Patients; Pharmacokinetics; Pharmacology/Toxicology; Pregnancy; Prospective Studies; Sarcoma, Ewing - drug therapy; Sarcoma, Ewing - metabolism; Sex Characteristics; Sex differences; Young Adult; Adolescent and young adult; Pharmacokinetics modelling; Ewing sarcoma; Osteosarcoma; Hodgkin’s lymphoma; Gender; Doxorubicin; Doxorubicinol
• DOI: 10.1007/s00280-018-3683-8
• ISSN: 0344-5704; 1432-0843

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.