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.
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Posted 13 May, 2020
Invitations sent on 06 May, 2020
On 06 May, 2020
Received 06 May, 2020
On 30 Apr, 2020
On 29 Apr, 2020
On 15 Aug, 2019
On 24 Apr, 2020
On 18 Dec, 2019
Received 18 Dec, 2019
Invitations sent on 09 Dec, 2019
On 08 Dec, 2019
On 07 Dec, 2019
On 07 Dec, 2019
On 26 Nov, 2019
Received 08 Oct, 2019
Received 08 Oct, 2019
On 08 Oct, 2019
On 06 Oct, 2019
Invitations sent on 28 Aug, 2019
On 15 Aug, 2019
On 15 Aug, 2019
On 31 Jul, 2019
On 29 Jul, 2019
Posted 13 May, 2020
Invitations sent on 06 May, 2020
On 06 May, 2020
Received 06 May, 2020
On 30 Apr, 2020
On 29 Apr, 2020
On 15 Aug, 2019
On 24 Apr, 2020
On 18 Dec, 2019
Received 18 Dec, 2019
Invitations sent on 09 Dec, 2019
On 08 Dec, 2019
On 07 Dec, 2019
On 07 Dec, 2019
On 26 Nov, 2019
Received 08 Oct, 2019
Received 08 Oct, 2019
On 08 Oct, 2019
On 06 Oct, 2019
Invitations sent on 28 Aug, 2019
On 15 Aug, 2019
On 15 Aug, 2019
On 31 Jul, 2019
On 29 Jul, 2019
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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