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Research article
Joachim Boos
Universitatsklinikum Munster Padiatrische Hamatologie und Onkologie
Corresponding Author
ORCiD: https://orcid.org/0000-0003-2954-2025
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Despite its cardiotoxicity doxorubicin is widely used for the treatment of paediatric malignancies. Current treatment regimens appear to be suboptimal as treatment strategies vary and do not follow a clear pharmacological rationale. Standardisation of dosing strategies in particular for infants and younger children is required but is hampered by scarcely defined exposure-response relationships. The aim is to provide a rational dosing concept allowing for a reduction of variability in systemic therapy intensity and subsequently unforeseen side effects.
Methods: Doxorubicin plasma concentrations in paediatric cancer patients were simulated for different treatment schedules using a population pharmacokinetic model which considers age-dependent differences in doxorubicin clearance. Overall drug exposure and peak concentrations were assessed. Simulation results were used to support a three round Delphi consensus procedure with the aim to clarify the pharmacological goals of doxorubicin dosing in young children. A group of 28 experts representing paediatric trial groups and clinical centres were invited to participate in this process.
Results: Pharmacokinetic simulations illustrated the substantial differences in therapy intensity associated with current dosing strategies. Consensus among the panel members was obtained on a standardised a priori dose adaptation that individualises doxorubicin doses based on age and body surface area targeting uniform drug exposure across children treated with the same protocol. Further, a reduction of peak concentrations in very young children by prolonged infusion was recommended.
Conclusions: An approach to standardise current dose modification schemes in young children is proposed. The consented concept takes individual pharmacokinetic characteristics into account and involves adaptation of both the dose and the infusion duration potentially improving the safety of doxorubicin administration.
Keywords
doxorubicin, children, cardiotoxicity, pharmacokinetics, Delphi procedure
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CURRENT STATUS: Under Review
Version 3
Posted 13 May, 2020
No community comments so far
Reviewers invited
Invitations sent on 06 May, 2020
Reviewer #1 agreed
On 06 May, 2020
Review #1 received
Received 06 May, 2020
Editor assigned
On 30 Apr, 2020
Editor invited
On 29 Apr, 2020
Submission checks complete
On 15 Aug, 2019
No comments provided
Editorial decision: Minor revision
On 24 Apr, 2020
Reviewer #1 agreed
On 18 Dec, 2019
Review #1 received
Received 18 Dec, 2019
Reviewers invited
Invitations sent on 09 Dec, 2019
Editor assigned
On 08 Dec, 2019
Submission checks complete
On 07 Dec, 2019
Editor invited
On 07 Dec, 2019
No comments provided
Editorial decision: Major revision
On 26 Nov, 2019
Review #2 received
Received 08 Oct, 2019
Review #1 received
Received 08 Oct, 2019
Reviewer #2 agreed
On 08 Oct, 2019
Reviewer #1 agreed
On 06 Oct, 2019
Reviewers invited
Invitations sent on 28 Aug, 2019
Submission checks complete
On 15 Aug, 2019
Editor invited
On 15 Aug, 2019
Editor assigned
On 31 Jul, 2019
First submitted
On 29 Jul, 2019
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This preprint is under consideration at BMC Pharmacology and Toxicology. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Joachim Boos
Universitatsklinikum Munster Padiatrische Hamatologie und Onkologie
Corresponding Author
ORCiD: https://orcid.org/0000-0003-2954-2025
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 3
Posted 13 May, 2020
No community comments so far
Reviewers invited
Invitations sent on 06 May, 2020
Reviewer #1 agreed
On 06 May, 2020
Review #1 received
Received 06 May, 2020
Editor assigned
On 30 Apr, 2020
Editor invited
On 29 Apr, 2020
Submission checks complete
On 15 Aug, 2019
No comments provided
Editorial decision: Minor revision
On 24 Apr, 2020
Reviewer #1 agreed
On 18 Dec, 2019
Review #1 received
Received 18 Dec, 2019
Reviewers invited
Invitations sent on 09 Dec, 2019
Editor assigned
On 08 Dec, 2019
Submission checks complete
On 07 Dec, 2019
Editor invited
On 07 Dec, 2019
No comments provided
Editorial decision: Major revision
On 26 Nov, 2019
Review #2 received
Received 08 Oct, 2019
Review #1 received
Received 08 Oct, 2019
Reviewer #2 agreed
On 08 Oct, 2019
Reviewer #1 agreed
On 06 Oct, 2019
Reviewers invited
Invitations sent on 28 Aug, 2019
Submission checks complete
On 15 Aug, 2019
Editor invited
On 15 Aug, 2019
Editor assigned
On 31 Jul, 2019
First submitted
On 29 Jul, 2019
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Despite its cardiotoxicity doxorubicin is widely used for the treatment of paediatric malignancies. Current treatment regimens appear to be suboptimal as treatment strategies vary and do not follow a clear pharmacological rationale. Standardisation of dosing strategies in particular for infants and younger children is required but is hampered by scarcely defined exposure-response relationships. The aim is to provide a rational dosing concept allowing for a reduction of variability in systemic therapy intensity and subsequently unforeseen side effects.
Methods: Doxorubicin plasma concentrations in paediatric cancer patients were simulated for different treatment schedules using a population pharmacokinetic model which considers age-dependent differences in doxorubicin clearance. Overall drug exposure and peak concentrations were assessed. Simulation results were used to support a three round Delphi consensus procedure with the aim to clarify the pharmacological goals of doxorubicin dosing in young children. A group of 28 experts representing paediatric trial groups and clinical centres were invited to participate in this process.
Results: Pharmacokinetic simulations illustrated the substantial differences in therapy intensity associated with current dosing strategies. Consensus among the panel members was obtained on a standardised a priori dose adaptation that individualises doxorubicin doses based on age and body surface area targeting uniform drug exposure across children treated with the same protocol. Further, a reduction of peak concentrations in very young children by prolonged infusion was recommended.
Conclusions: An approach to standardise current dose modification schemes in young children is proposed. The consented concept takes individual pharmacokinetic characteristics into account and involves adaptation of both the dose and the infusion duration potentially improving the safety of doxorubicin administration.
Figure 1
Figure 2
Figure 3
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