Systemic exposure to 5‐fluorouracil and its metabolite, 5,6‐dihydrofluorouracil, and development of a limited sampling strategy for therapeutic drug management of 5‐fluorouracil in patients with gastrointestinal malignancy

• Published in: British journal of clinical pharmacology 2021-03, Vol.87 (3), p.937-945
• Main Authors: Jacob, Jeana, Mathew, Sumith K., Chacko, Raju Titus, Aruldhas, Blessed Winston, Singh, Ashish, Prabha, Ratna, Mathew, Binu Susan
• Format: Article
• Language: English
• Subjects: 5,6‐dihydrofluorouracil; area under the curve; DHFU Tmax; drug monitoring; fluorouracil; limited sampling strategy; pharmacokinetics
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.14444

Aims 5‐Fluorouracil (5‐FU) is widely used in combination chemotherapy, and literature suggests pharmacokinetic‐guided dosing to improve clinical efficacy and reduce toxicity. This study aimed to determine the pharmacokinetic exposure of both 5‐FU and its metabolite, 5,6‐dihydrofluorouracil (DHFU), in patients with gastrointestinal malignancy and to establish a simplified strategy to assist in therapeutic drug management for dose optimization. Methods This was a prospective, observational study, performed in 27 patients diagnosed with gastrointestinal malignancy who were prescribed 5‐FU. Multiple samples were collected per patient over the slow bolus (15–20 min) and continuous infusion period (over 44 h) in doses 1 and 3, and the concentrations of 5‐FU and DHFU were measured. Results A higher proportion of patients had exposures within the therapeutic range in dose 3 (50%) as compared to dose 1 (37.5%) with 5‐FU. There was an association between delayed time to maximum concentration of DHFU and a high maximum concentration of 5‐FU. A limited sampling strategy was developed with 4 samples, 2 during the bolus period and 2 during the continuous period (at 18 h and the end of infusion), which accurately predicted the total area under the curve of 5‐FU. Conclusion Using body surface area‐based dosing with 5‐FU, 50–60% of patients were outside of the therapeutic range. In the absence of genotype testing, measurement of the metabolite DHFU could be a phenotypical measure of dihydropyrimidine dehydrogenase enzyme activity. A limited sampling strategy was developed in patients who were prescribed a combination regimen of slow bolus, followed by a 44‐hour continuous infusion of 5‐FU to assist in the therapeutic drug management of patients.