Influence of the skeletal muscle index on pharmacokinetics and toxicity of fluorouracil.

BACKGROUND: The body composition of patients has been associated with tolerability and effectiveness of anticancer therapy. This study aimed to assess the influence of the skeletal muscle index (SMI) on the pharmacokinetics and toxicity of fluorouracil. METHODS: Patients treated in an oncological practice with fluorouracil-based chemotherapy and undergoing therapeutic drug monitoring were retrospectively investigated. Computed tomography images were analyzed to measure abdominal skeletal muscle areas in Hounsfield units for the psoas major muscle, back and total skeletal muscle to determine the SMI. For the latter, an automated segmentation method was used additionally. SMI measures were tested as covariates on fluorouracil clearance in a population pharmacokinetic model. Furthermore, regression analyses were performed to analyze the influence of SMI measures on the probability of clinically relevant adverse events (CTCAE grades ≥ 2). RESULTS: Fluorouracil plasma concentrations of 111 patients were available. Covariate analyses showed significant improvements of the model fit by all SMI measures. However, interindividual variability of fluorouracil clearance was only slightly reduced, whereas the SMI of the back muscle showed the largest reduction (-1.1 percentage points). Lower SMI values of the back muscle increased the probability for polyneuropathy and lower SMI of the psoas increased the probability for fatigue. CONCLUSIONS: Our results suggest that pharmacokinetics and toxicity of fluorouracil may be associated with specific SMI measures which deserve further investigation.

Current status and future outlooks on therapeutic drug monitoring of fluorouracil.

INTRODUCTION: Therapeutic drug monitoring (TDM) of the anticancer drug fluorouracil (5FU) as a method to support dose adjustments has been researched and discussed extensively. Despite manifold evidence of the advantages of 5FU-TDM, traditional body surface area (BSA)-guided dosing is still widely applied. AREAS COVERED: This review covers the latest evidence on 5FU-TDM based on a literature search in PubMed between June and September 2021. It particularly highlights new approaches of implementing 5FU-TDM into precision medicine by combining TDM with pharmacogenetic testing and/or pharmacometric models. This review further discusses remaining obstacles in order to incorporate 5FU-TDM into clinical routine. EXPERT OPINION: New data on 5FU-TDM further strengthen the advantages compared to BSA-guided dosing as it is able to reduce pharmacokinetic variability and thereby improve treatment efficacy and safety. Interprofessional collaboration has the potential to overcome the remaining barriers for its implementation. Preemptive pharmacogenetic testing followed by 5FU-TDM can further improve 5FU exposure in a substantial proportion of patients. Developing a model framework integrating pharmacokinetics and pharmacodynamics of 5FU will be crucial to fully advance into the precision medicine era. Model applications can potentially support clinicians in dose finding before starting chemotherapy. Additionally, TDM provides further assistance in continuously improving model predictions.