In a prospective, multicentre Dutch Pharmacology Oncology Group – Therapeutic Drug Monitoring study conducted in 600 patients with cancer who were treated with 24 different oral targeted therapies, 53% of patients were underexposed at a certain time point during treatment. The study team showed that pharmacokinetically guided interventions could be performed in 56.5% of these patients which resulted in target attainment without additional toxicities in 74.3% of the patients. Therefore, pharmacokinetically guided dose optimisation of oral targeted therapies is feasible in clinical practice and markedly reduced the proportion of underexposed patients. The authors led by Dr. Neeltje Steeghs of The Netherlands Cancer Institute in Amsterdam published their findings on 28 June 2022 in the Annals of Oncology and emphasised that efforts should be made to provide access to therapeutic drug monitoring for each individual patient treated with oral targeted therapies.
Although oral anticancer treatment comes with many advantages, including the possibility of outpatient treatment and being more convenient for patients, a major drawback of oral targeted therapies is their high interindividual variability in exposure, with coefficients of variation typically around 40-70%. Many factors contribute to this high variability, including poor pharmaceutical formulations (as low bioavailability results in high inter- and intra-individual variability in exposure), drug-drug and drug-food interactions, patient non-adherence, genetic polymorphisms in metabolising enzymes, and (patho-)physiological differences between patients resulting in altered pharmacokinetics.
The authors wrote in background that systemic exposure to many of these drugs is related to both efficacy and toxicity. As a result, administration of oral targeted therapies at the currently approved fixed doses has the undesirable effect that a substantial part of patients is being treated outside the therapeutic window. Supratherapeutic exposure can cause unnecessary toxicities in some patients, whereas underexposure, resulting in suboptimal efficacy, is an even more frequently encountered problem and remains often unnoticed.
The authors also commented that rational precision medicine would not only include selecting the right drug based on molecular characteristics of the tumour, but also by selecting the right dose for each patient. By use of therapeutic drug monitoring, which is adjusting the dose based on measured drug levels, the right dose could be selected for each individual patient, thereby optimising tumour exposure to the drug. To apply therapeutic drug monitoring in clinical practice, practical guidelines on pharmacokinetic targets need to be available. Furthermore, an adequate infrastructure for sample collection, shipment, bioanalysis, interpretation, and reporting of results should be in place, with a short turn-around time.
Previous feasibility studies have already demonstrated that pharmacokinetically guided dosing of pazopanib and sunitinib is a promising tool to achieve therapeutic exposure in a larger proportion of patients. To further evaluate the feasibility of therapeutic drug monitoring, the study team set up the Dutch Pharmacology Oncology Group – Therapeutic Drug Monitoring study, which is an ongoing, prospective protocol providing a framework to investigate the feasibility, tolerability, and efficacy of individualised dosing for multiple oral targeted therapies simultaneously.
Primary outcome was to halve the proportion of underexposed patients, compared with historical data. Pharmacokinetic sampling was performed after 4, 8, and 12 weeks, and every 12 weeks thereafter. In case of Cmin below the predefined target and manageable toxicity, a pharmacokinetically guided intervention was proposed (i.e. checking compliance and drug-drug interactions, concomitant intake with food, splitting intake moments or dose increments).
In total, 600 patients were included of whom 426 patients were evaluable for the primary outcome and 552 patients had at least 1 pharmacokinetic sample available and were therefore evaluable for the overall analyses. Pharmacokinetically guided dosing reduced the proportion of underexposed patients at the third pharmacokinetic measurement by 39.0% (95% confidence interval 28.0-49.0%) compared with historical data. At the third pharmacokinetic measurement, 110 of 426 patients (25.8%) had a low exposure. In total, 294 patients (53.3%) had at least 1 pharmacokinetic sample below the preset target at a certain time point during treatment. In 166 of these patients (56.5%), pharmacokinetically guided interventions were performed, which were successful in 113 of 152 evaluable patients (74.3%).
The authors commented that their results show that pharmacokinetically guided dose individualisation is feasible in clinical practice. The proportion of underexposed patients at the third pharmacokinetic measurement was reduced by 39.0% compared with historical data, not reaching primary endpoint of 50%. Overall, more than half of the patients had a low exposure at a certain time point during treatment. In more than half of these patients it was feasible to implement a pharmacokinetically guided intervention, which was successful in the majority of patients. Overall, successful pharmacokinetically guided interventions were performed in 20.5% of patients, while an additional 46.7% of patients had an adequate exposure at all time, thus not needing any intervention.
Reference
Groenland SL, van Eerden RAG, Westerdijk K, et al. Therapeutic drug monitoring based precision dosing of oral targeted therapies in oncology: a prospective multicentre study. Annals of Oncology; Published online 28 June 2022. DOI: https://doi.org/10.1016/j.annonc.2022.06.010
