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. 2024 Dec;63(12):1711-1722.
doi: 10.1007/s40262-024-01445-5. Epub 2024 Nov 16.

A Population Pharmacokinetic Study to Evaluate Doxorubicin Exposure Across All Age Groups

Ma Ida Mohmaed Ali  1   2 , A Laura Nijstad  3 , René J Boosman  4   5 , Marie-Rose B S Crombag  3 , Shelby Barnett  6 , Gareth J Veal  6 , Arief Lalmohamed  7   8 , Nielka P van Erp  9 , Neeltje Steeghs  10 , C Michel Zwaan  11   12 , Jos H Beijnen  4   5   8 , Hinke Siebinga  4   5 , Alwin D R Huitema  4   5   7   13
Affiliations

A Population Pharmacokinetic Study to Evaluate Doxorubicin Exposure Across All Age Groups

Ma Ida Mohmaed Ali et al. Clin Pharmacokinet. 2024 Dec.

Abstract

Background: The effect of age on doxorubicin pharmacokinetics remains inconclusive, especially in patients at the extremes of the age spectrum. We developed a population pharmacokinetic model to further investigate the impact of age on the pharmacokinetics of doxorubicin.

Methods: A three-compartment model, incorporating allometric scaling was developed to describe doxorubicin pharmacokinetics across all ages. First, the effect of age in young patients was investigated, by adding a maturation function on clearance (CL), the central compartment (V1) and peripheral compartments (V2 and V3). Second, the impact of ageing was investigated by adding a maximal effect (Emax) function on CL, V1, V2, and V3. To investigate the overall impact of age on doxorubicin exposure, various simulations were conducted.

Results: A total of 168 patients (age: 0.11-90 years) with 555 doxorubicin samples were included. The maturation function was relevant for V1 and V2 (13.1 and 23.7 L, respectively), leading to an increase in V1 and V2 with increasing age. In contrast, adding an Emax function only impacted V3 (1063L), resulting in a decrease of V3 with age. Simulations showed no clinically relevant difference in the exposure of doxorubicin between age groups.

Conclusion: A population pharmacokinetic model with data across the age range showed that age predominantly affected volumes of distribution of the central and peripheral compartments. These effects were not considered to be clinically relevant based on performed simulations. This supports the use of currently used doxorubicin dosages of 1 mg/kg for infants and toddlers < 10 kg and body surface area-based dosing for other patients.

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Conflict of interest statement

Declarations. Funding: The UK study was supported in part by Cancer Research UK, the Experimental Cancer Medicine Centre Network and the Little Princess Trust. The studies in the Netherlands did not receive any specific grant from funding agencies in public, commercial, or not-for-profit sectors. Conflict of interest: The authors declared no competing interests in this work. Jos Beijnen and Alwin D.R. Huitema are Editorial Board members of Clinical Pharmacokinetics. Jos Beijnen and Alwin Huitema were not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Ethics approval: Ethical approval for the study in elderly patients in the Netherlands was approved by the Medical Ethical Committee (METC) of the Slotervaart Hospital, the Netherlands (file identifier: Dutch Trial register 3964704812). For the study in children in the Netherlands, the study was ethically approved by the METC of the Erasmus MC (NL63037.078.18). For the study in children in Newcastle, the study was approved by the North East – Newcastle & North Tyneside 2 Research Ethics Committee (ISRCTN 10139334; REC 18/NE/0384). Informed consent: Informed consent was obtained from all patients, parents or guardians in writing. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request. Consent for publication: Not applicable Code availability: The NM-TRAN control stream is available in the supplementary materials. Author contributions: M.I. Mohmaed Ali: investigation, formal analysis, writing: original draft. A.L. Nijstad: conceptualization, investigation, writing: Review & Editing. R.J. Boosman: investigation, writing: Review & Editing, M.B.S. Crombag: conceptualization, writing: Review & Editing, S. Barnett: conceptualization, writing: Review & Editing, G.J. Veal: conceptualization, writing: Review & Editing, A. Lalmohamed: writing: Review & Editing, N.P. van Erp: conceptualization, writing: Review & Editing, N. Steeghs: writing: Review & Editing, C.M. Zwaan: conceptualization, writing: Review & Editing, J.H. Beijnen: writing: Review & Editing, H. Siebinga: writing: Review & Editing, supervision, A.D.R. Huitema: conceptualization, writing: Review & Editing, supervision.

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