Utilisation of therapeutic drug monitoring (TDM) approaches for the treatment of neonates and children with cancer

G. J. Veal. Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UNITED KINGDOM

Introduction: Over the past 15 years the Newcastle Cancer Centre Pharmacology Group (NCCPG) have conducted a portfolio of studies designed to determine key factors which influence the efficacy of anticancer drugs, focusing on how this information can be used to optimise the treatment of childhood cancer1,2. Defining chemotherapy dosing regimens for neonates with cancer is particularly challenging and commonly not standardized based on any scientific rationale. The NCCPG provide a national therapeutic drug monitoring (TDM) service to guide treatment in such challenging patient populations. As an example of this approach to treatment, we report on the use of carboplatin TDM in preterm and full-term neonates, anephric patients and children receiving high dose chemotherapy.

Method: Carboplatin TDM was performed to achieve target drug exposures (AUC values) in 9 preterm and full-term neonates diagnosed with retinoblastoma, 4 patients with bilateral nephrectomy diagnosed with Wilms’ tumour and 12 patients receiving high dose chemotherapy for the treatment of rhabdomyosarcoma at centres across the UK. Carboplatin was administered over 3-5 days of treatment with TDM utilized to target cumulative AUC values of 5-20mg/ml.min depending on treatment protocol. This involved the collection of blood samples on day 1 of carboplatin treatment and overnight courier to Newcastle for real-time sample analysis. Carboplatin levels were determined by atomic absorption spectrometry as previously described3 and dose modifications on days 2-5 of treatment carried out as required.

Results: AUC values achieved following TDM were within 15% of target values in >95% of cases, with dose modifications up to 220% required to achieve target AUC values, based on initial protocol-based dosing schedules.Carboplatin clearance determined across consecutive chemotherapy courses in two neonates increased from 3.4-7.1ml/min and 7.2-16.5ml/min (>2-fold increases over several weeks of treatment), reflecting early renal function maturation. Carboplatin was well tolerated, with TDM approaches limiting the likelihood of patients experiencing serious adverse effects commonly associated with treatment.

Conclusion: The study highlights the benefits of utilising TDM to achieve cumulative target carboplatin AUC values in challenging patient groups including neonates, particularly in view of marked increases in drug clearance observed during the first weeks of life. TDM approaches should be more widely utilised in oncology, to guide dosing in patients where unpredictable pharmacokinetic profiles may be anticipated.

References: 1. Veal GJ et al. (2016). Cancer Chemother Pharmacol 77: 685-692. 2. Hill CR et al. (2014). Clin Pharmacokinet 53: 741-751. 3. Veal GJ et al. (2015). Eur J Cancer 51: 2022-2030.