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

Ma Ida Mohmaed Ali*, A. Laura Nijstad, René J. Boosman, Marie Rose B.S. Crombag, Shelby Barnett, Gareth J. Veal, Arief Lalmohamed, Nielka P. van Erp, Neeltje Steeghs, C. Michel Zwaan, Jos H. Beijnen, Hinke Siebinga, Alwin D.R. Huitema

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)1711-1722
Number of pages12
JournalClinical Pharmacokinetics
Volume63
Issue number12
Early online date16 Nov 2024
DOIs
Publication statusPublished - Dec 2024

Bibliographical note

Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024.

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.

FundersFunder number
Cancer Research UK
Experimental Cancer Medicine Centre Network
Little Princess Trust

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