Pharmacokinetics and Therapeutic Monitoring in Colorectal Cancer

Pharmacokinetics examines the absorption, distribution, metabolism and excretion of anticancer agents, with particular emphasis in colorectal cancer on fluoropyrimidines such as 5-fluorouracil (5-FU) and its oral prodrug capecitabine. Interindividual variability in drug clearance and activation pathways often leads to under- or overexposure, compromising efficacy or provoking severe toxicity. Therapeutic drug monitoring (TDM) aims to tailor dosing by measuring plasma or tissue concentrations and adjusting regimens to achieve a target exposure, most commonly defined by the area under the plasma concentration–time curve (AUC). Precision dosing strategies seek to improve objective response rates, reduce grade 3–4 toxicities and inform the development of robust analytical and modelling tools for real-time dose optimisation. Advances in analytical chemistry and pharmacometric modelling have underpinned a move from empirical body surface area (BSA)-based dosing towards more personalised, exposure-guided approaches.

Research from Nature Portfolio

Recent studies have demonstrated that a pharmacokinetically guided dosing algorithm for 5-FU significantly enhances treatment responses compared with traditional BSA-based regimens. A meta-analysis of prospective controlled trials showed that exposure-driven adjustments improved objective response rates and substantially lowered the incidence of severe (grade 3–4) haematological and gastrointestinal adverse events. This work supports the adoption of precision chemotherapy through real-time AUC monitoring and dose recalibration.

Efforts to facilitate TDM have yielded a sensitive ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) assay capable of simultaneous quantification of 5-FU, uracil and the prodrug tegafur in human plasma. Validation under regulatory guidance confirmed linearity, accuracy and precision across clinically relevant concentration ranges. Applied to patients receiving combination therapy after hepatectomy, this method revealed individual concentration–time profiles, highlighting its potential to guide personalised dose adjustments and reduce toxicity in colorectal liver metastasis management.

Pharmacokinetics and Therapeutic Monitoring in Colorectal Cancer publication trend

The graph below shows the total number of articles in pharmacokinetics and therapeutic monitoring in colorectal cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Pharmacokinetics: The study of how a drug is absorbed, distributed, metabolised and excreted by the body.

Therapeutic drug monitoring (TDM): Measurement of drug or metabolite levels in biological fluids to guide dosage adjustments and optimise safety and efficacy.

Area under the curve (AUC): The integral of the concentration–time profile, representing the total drug exposure over a dosing interval.

Body surface area (BSA): A patient-specific metric calculated from height and weight, traditionally used to determine chemotherapy doses.

Prodrug: An inactive precursor converted in vivo into an active pharmacological agent, as in capecitabine to 5-FU.

Ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS): A high-sensitivity analytical technique combining rapid chromatographic separation with mass-based detection for precise quantification of drugs and metabolites.

References

1. Pharmacokinetically guided algorithm of 5-fluorouracil dosing, a reliable strategy of precision chemotherapy for solid tumors: a meta-analysis. Scientific Reports (2016).
2. Simultaneous quantification method for 5-FU, uracil, and tegafur using UPLC-MS/MS and clinical application in monitoring UFT/LV combination therapy after hepatectomy. Scientific Reports (2021).
3. Determination of Capecitabine and Its Metabolites in Plasma of Egyptian Colorectal Cancer Patients. Analytica—A Journal of Analytical Chemistry and Chemical Analysis (2023).
4. Prediction of exposure-driven myelotoxicity of continuous infusion 5-fluorouracil by a semi-physiological pharmacokinetic–pharmacodynamic model in gastrointestinal cancer patients. Cancer Chemotherapy and Pharmacology (2020).
5. A Sensitive and Efficient Method for Determination of Capecitabine and Its Five Metabolites in Human Plasma Based on One‐Step Liquid‐Liquid Extraction. Journal of Analytical Methods in Chemistry (2019).