Pharmacokinetic Targets for Therapeutic Drug Monitoring of Small Molecule Kinase Inhibitors in Pediatric Oncology

Abstract

In recent years new targeted small molecule kinase inhibitors have become available for pediatric patients with cancer. Relationships between drug exposure and treatment response have been established for several of these drugs in adults. Following these exposure–response relationships, pharmacokinetic (PK) target minimum plasma rug concentration at the end of a dosing interval (Cmin) values to guide therapeutic drug monitoring (TDM) in adults have been proposed. Despite the fact that variability in PK may be even larger in pediatric patients, TDM is only sparsely applied in pediatric oncology. Based on knowledge of the PK, mechanism of action, molecular driver, and pathophysiology of the disease, we bridge available data on the exposure–efficacy relationship from adults to children and propose target Cmin values to guide TDM for the pediatric population. Dose adjustments in individual pediatric patients can be based on these targets. Nevertheless, further research should be performed to validate these targets.

The Changing Face of Oncology Research, Drug Development, and Clinical Practice: Toward Patient‐Focused Precision Therapeutics

“…Pediatric TDM targets for targeted kinase inhibitors have been recently proposed, applying principles of extrapolation. 13 Although primarily in a population with nonmalignant disease receiving treosulfan-based conditioning prior to allogeneic hematopoietic stem cell transplant, estimation of nonmonotonic exposure-response relationships for complex outcomes (mortality-free engraftment) enabled definition of an optimal exposure range for pediatric TDM. 14 Whereas these examples are illustrative of hypothesis generation for TDM, equally crucial for clinical translation are innovations in model-informed clinical decision support systems for deployment of TDM and downstream patient management in clinical practice.…”

On precision dosing of oral small molecule drugs in oncology

“…Data from the exposure–response relationship studies can be described using various forms of regression analysis or more simply by comparing the outcomes of patients stratified by, for example, C min quartiles or deciles 30,33–35 . Ultimately, the goal of such studies is to define a therapeutic exposure range below which there is increased risk of lack of efficacy and above which there is increased risk of toxicity 2–6 …”

“…Once drug exposure–response studies successfully define a target therapeutic concentration range or efficacy cut‐off, prospective dose‐adjustment trials intended to demonstrate that TDM can be implemented should be initiated (Figure 1, Stage 3). The primary outcome of this type of study is the proportion of patients starting the treatment under‐ or over‐exposed who successfully achieve therapeutic blood drug levels following recommendations for dose adjustments 2–6,37–40 . Such TDM feasibility studies may compare the prevalence of therapeutic exposure before and after dose adjustment recommendation in the same group of subjects or, preferably, with a separate control arm.…”

“…As mentioned above, numerous examples of such studies evaluating feasibility of TDM for oral small molecule anticancer drugs are available and many of them indeed succeed in increasing the proportion of patients with drug levels in the therapeutic range 2–6,37–40 . An example that deserves special mention is the recently described study of the Dutch Pharmacology Oncology Group 38 .…”

“…For such drugs, a flat‐fixed dose will be optimal for only a fraction of patients. Numerous oral small molecule anticancer drugs that are already in clinical use have been shown to exhibit such high interpatient PK variabilities and strong PK–pharmacodynamics (PD) relationships, and seem to be strong candidates for benefiting from TDM as described in several excellent reviews on this subject 2–6 …”