Optimizing exposure of oral targeted therapies in oncology : Towards precision dosing

Abstract

Targeted therapies have been a major breakthrough in the treatment of cancer. With the introduction of these small molecules, that inhibit specific driver proteins in growth signal transduction pathways, the focus has increasingly shifted towards precision medicine, by selecting the right drug for individual patients based on molecular characteristics of their tumor. However, nowadays these drugs are still administered using a one-size-fits-all fixed dosing approach, while convincing arguments advocate for precision dosing instead. First, there is a weak basis for the registered dose. Second, interindividual variability in pharmacokinetic (PK) exposure is high. Most importantly, many of these new oral targeted therapies have a narrow therapeutic window. As a result, the problem with the currently used fixed dosing regimen is that ± 30% of patients is being underdosed and thus at risk for suboptimal treatment efficacy, whereas ± 15% of patients are currently being overdosed, potentially resulting in unnecessary toxicities. Hence, rational precision medicine would not only include selecting the right drug, but also selecting the right dose. Precision dosing can be achieved by selecting the right starting dose for each individual (group of) patients(s), after which this dose can be further optimized by PK-guided dosing, i.e. adjusting the dose based on measured drug concentrations. This thesis focuses on the rationale, the evidence and the clinical application of precision dosing of oral targeted therapies in oncology. First, prerequisites for the rational application of PK-guided dosing are discussed and the need for randomized trials is questioned. Then, it is demonstrated that exposure to several oral targeted therapies is related to efficacy in real-life patient cohorts. Subsequently, several studies are described in which precision dosing was applied in clinical practice. A large nationwide prospective study in the Netherlands, in which 600 patients were included, showed that PK-guided dosing was feasible in clinical practice for most compounds and reduced the proportion of underexposed patients. These findings support the introduction of PK-guided dosing as standard of care. Furthermore, alternative strategies for precision dosing are highlighted, focusing on cost-neutral interventions (i.e. splitting intake moments and concomitant intake with food), drug-drug interactions and bioavailability.