Consensus on doxorubicin dosing in infants and children: pharmacokinetic simulations and Delphi process
C. Siebel (1), G. Würthwein (1), C. Lanvers-Kaminsky (1), G. Hempel (2), J. Boos (1)
(1) Department of Paediatric Haematology and Oncology, University Children’s Hospital of Muenster, Muenster, Germany; (2) Department of Pharmaceutical and Medical Chemistry - Clinical Pharmacy, University of Muenster, Muenster, Germany
Objectives: Despite their cumulative dose-dependent cardiotoxicity anthracyclines, such as doxorubicin, are still a mainstay for the treatment of both adult and paediatric cancer. However, dose recommendations especially in young patients have been developed more empirically rather than being based on pharmacological data. Large differences exist in doxorubicin dose and infusion time between paediatric treatment protocols and dose reduction strategies for infants vary largely between the different protocols. In a selection of treatment protocols that were evaluated in this study doxorubicin dose range was 15 – 50 mg/m² and infusion time varied from 15 min to 48 h. As the prevention of chronic cardiac side effects receives more attention with the growing number of childhood cancer survivors, we ask how population pharmacokinetic (PK) simulations in combination with a Delphi approach could aid in developing more rational dosing strategies for doxorubicin in paediatric patients.
Methods: A model-informed process was developed based on an already published population PK model for doxorubicin (described in [1]). In brief, pharmacokinetic data from 94 paediatric cancer patients (aged 0.2 – 17.7 years) from the EPOC-MS-001-Doxo trial (EudraCT-Nr: 2009-011454-17) were evaluated to develop the model. According to this model doxorubicin clearance was linearly scaled to BSA with an additional power function of age on clearance. Based on the model Monte Carlo simulations were performed using NONMEM version 7.3 [2] to visualize the influence of differences in patient age and body composition on therapy intensity represented by AUC and cmax. Particular attention was drawn to the influence of various dose reduction strategies in infants and very young children. Further, alternative dose reduction strategies were developed that should allow achieving distinct AUC and cmax goals. For simulations generic children according to WHO and CDC growth charts were used and model parameters were fixed to the published final parameter estimates. Based on the simulation results a three-round Delphi approach was initiated. In this Delphi approach 28 expert clinicians (EPOC partners and selected clinical trial leaders) were asked to provide their opinion on
- the goals of doxorubicin dose reductions within single protocols and
- common PK targets between different protocols that might guide the administration of doxorubicin.
As background information the participants of the Delphi process were provided with the simulation results.
Results: Considerable differences in individual therapy intensity have been observed within currently applied paediatric treatment protocols. When taking the CWS-2002/CWSSoTiSaR protocol (dose: 20 mg/m², dose reduction in children < 1 year or weighing < 10 kg; infusion time: 3 h) as an example, AUC and cmax values are lowest in neonates (AUC = 507 µg*h/L, cmax = 57 µg/L), increase towards a maximum in children slightly above one year of age (AUC = 1002 µg*h/L, cmax = 138 µg/L) and then steadily declines in older children. The simulations further suggest that by adjusting the doxorubicin dose to age and BSA the individual therapy intensity can be tailored towards specific goals. Of note, AUC and cmax values are subject to a substantial amount of inter-patient variability which needs to be taken into account when developing standardized dose reduction strategies that are based upon previously specified AUC and cmax goals. The first round of the Delphi process was completed by 8 of the 28 panellists, the second round was completed by 8 of the 28 panel members. Evaluation for consensus is still ongoing in a third round of the process.
Conclusions: Adjusting the doxorubicin dose to achieve defined therapy intensity goals in infants and young children may help to reduce the risk of chronic cardiac side effects while maintaining tumour efficacy. A simulation process in combination with a Delphi approach was conducted to establish a consensus for doxorubicin dosing rules in paediatric patients. Consented dosing rules need to be prospectively validated in a clinical trial.
References:
[1] Völler S, Boos J, Krischke M, Würthwein G, Kontny NE, Boddy AV, Hempel G. Age-Dependent Pharmacokinetics of Doxorubicin in Children with Cancer. Clinical Pharmacokinetics 2015; 54:1139–49.
[2] Beal, S., Sheiner, L.B., Boeckmann, A., & Bauer, R.J. NONMEM User's Guides. (1989-2011), Icon Development Solutions, Ellicott City, MD, USA, 2011.
