Over a decade of experience with carboplatin therapeutic drug monitoring in a childhood cancer setting in the United Kingdom

Abstract

The widely used platinum agent carboplatin represents a good example of an anticancer drug where clear relationships between pharmacological exposure and clinical response and toxicity have previously been shown. Within the setting of childhood cancer, there are defined groups of patients who present a particular challenge when dosing with carboplatin, including neonates and infants, those who are anephric, and poor prognosis patients receiving high‐dose chemotherapy. For these groups, nonstandard chemotherapy dosing regimens are currently utilised, often with different approaches between clinical study protocols and between treatment centres. For the treatment of these patient populations in the UK, there is now significant experience in carrying out therapeutic drug monitoring, aiming to consistently achieve target drug exposures, maximise drug efficacy and minimise treatment‐related side effects. An ongoing clinical trial is currently providing information on drug exposure for a wide range of anticancer agents in these hard to treat patient populations. In addition to supporting dosing decisions for individual patients, the collection and analysis of these data may allow the development of future dosing regimens. For example, current reduced dosing approaches for neonates and infants based on age or body weight, may well be better replaced by regimens based on a sound pharmacological rationale. The successful use of adaptive carboplatin dosing in childhood cancer should encourage the development of therapeutic drug monitoring approaches more widely in an oncology setting.

Clinical pharmacology of cytotoxic drugs in neonates and infants: Providing evidence-based dosing guidance

“…The glomerular filtration rate (GFR) is used to calculate the dose administered to patients, as proposed by Calvert and Newell [102,105]. These dosing equations are described in greater detail in a recent review by Barnett et al [106]. However, carboplatin dosing based on renal function poses a substantial challenge in neonates and infants because a reliable estimate of GFR is often unavailable.…”

“…This reflects the marked changes in GFR that occur within the first few months of life and the important role renal function plays in carboplatin elimination. Barnett et al recently compiled a summary of carboplatin dosing regimens used for various tumour types within the United Kingdom, including the dose reductions that are applied for the treatment for infants/neonates [106]. To illustrate, for low/intermediate-risk neuroblastoma, standard carboplatin dosing is 200 mg/m 2 to achieve a target AUC of 2.6 mg/mL)min per day.…”

Perspectives and Expertise in Establishing a Therapeutic Drug Monitoring Programme for Challenging Childhood Cancer Patient Populations

“…The utility of therapeutic drug monitoring (TDM) is widely used across a range of disease specialties and drug classes, including antibiotics, antipsychotics, anticonvulsants and immunosuppressants (14). However, it has remained an underused tool in an oncology setting, despite a number of published studies highlighting its potential clinical benefit (15)(16)(17)(18). More recently, studies supportive of TDM approaches for newer targeted anticancer drugs have been published (19)(20)(21)(22).…”

Precision medicine‐based drug treatment individualization in oncology

“…Early in the development of carboplatin, the relationship between drug exposure and efficacy and toxicity was established, and dosing was more accurately based on renal function (glomerular filtration rate [GFR]) than BSA. However, for specific groups such as infants, anephric patients, and those receiving high‐dose carboplatin, TDM dosing is more desirable that dosing based on (GFR) as summarized by Barnett et al 22 …”