Current status and future outlooks on therapeutic drug monitoring of fluorouracil

Schmulenson, Eduard; Zimmermann, Nigina; Mikus, Gerd; Joerger, Markus; Jaehde, Ulrich

doi:10.1080/17425255.2021.2029403

Cited by 4 publications

(3 citation statements)

References 193 publications

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“… 1 , 2 , 3 Typically, 5FU is dosed according to the patient's body surface area (BSA), resulting in a wide range of variability in 5FU plasma concentrations. 4 This pharmacokinetic variability may result individually in an insufficient response to 5FU therapy or intolerable toxicity, leading to treatment discontinuations. In fact, approximately 60% of patients treated with 5FU are reported being underdosed, whereas about 15% being overdosed when BSA‐based dosing is applied.…”

Section: Introductionmentioning

confidence: 99%

“…Fluorouracil (5FU) is still one of the cornerstones for the treatment of various solid tumors, particularly colorectal and head and neck cancer 1–3 . Typically, 5FU is dosed according to the patient's body surface area (BSA), resulting in a wide range of variability in 5FU plasma concentrations 4 . This pharmacokinetic variability may result individually in an insufficient response to 5FU therapy or intolerable toxicity, leading to treatment discontinuations.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…One adjunct to further improve precision medicine and reduce inter‐individual pharmacokinetic variability is the implementation of therapeutic drug monitoring (TDM), a concept well‐established in other specialties. Despite extensive research highlighting the advantages of TDM for 5‐fluorouracil (improved efficacy and safety), BSA remains the mainstay of dosing, 10 with limited access, inconvenience and cost of testing restricting uptake.…”

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confidence: 99%

Current colorectal cancer chemotherapy dosing limitations and novel assessments to personalize treatments

Arafat

Loft

Cao

et al. 2022

ANZ Journal of Surgery

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Pharmacogenetics of DPYD and treatment-related mortality on fluoropyrimidine chemotherapy for cancer patients: a meta-analysis and trial sequential analysis

de Moraes,

de Almeida Barbosa,

Sano

et al. 2024

BMC Cancer

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Background Fluoropyrimidines are chemotherapy drugs utilized to treat a variety of solid tumors. These drugs predominantly rely on the enzyme dihydropyrimidine dehydrogenase (DPD), which is encoded by the DPYD gene, for their metabolism. Genetic mutations affecting this gene can cause DPYD deficiency, disrupting pyrimidine metabolism and increasing the risk of toxicity in cancer patients treated with 5-fluorouracil. The severity and type of toxic reactions are influenced by genetic and demographic factors and, in certain instances, can result in patient mortality. Among the more than 50 identified variants of DPYD, only a subset has clinical significance, leading to the production of enzymes that are either non-functional or impaired. The study aims to examine treatment-related mortality in cancer patients undergoing fluoropyrimidine chemotherapy, comparing those with and without DPD deficiency. Methods The meta-analysis selected and evaluated 9685 studies from Pubmed, Cochrane, Embase and Web of Science databases. Only studies examining the main DPYD variants (DPYD*2A, DPYD p.D949V, DPYD*13 and DPYD HapB3) were included. Statistical Analysis was performed using R, version 4.2.3. Data were examined using the Mantel-Haenszel method and 95% CIs. Heterogeneity was assessed with I2 statistics. Results There were 36 prospective and retrospective studies included, accounting for 16,005 patients. Most studies assessed colorectal cancer, representing 86.49% of patients. Other gastrointestinal cancers were evaluated by 11 studies, breast cancer by nine studies and head and neck cancers by five studies. Four DPYD variants were identified as predictors of severe fluoropyrimidines toxicity in literature review: DPYD*2A (rs3918290), DPYD p.D949V (rs67376798), DPYD*13 (rs55886062) and DPYD Hap23 (rs56038477). All 36 studies assessed the DPYD*2A variant, while 20 assessed DPYD p.D949V, 7 assessed DPYD*13, and 9 assessed DPYDHap23. Among the 587 patients who tested positive for at least one DPYD variant, 13 died from fluoropyrimidine toxicity. Conversely, in the non-carrier group there were 14 treatment-related deaths. Carriers of DPYD variants was found to be significantly correlated with treatment-related mortality (OR = 34.86, 95% CI 13.96–87.05; p < 0.05). Conclusions This study improves our comprehension of how the DPYD gene impacts cancer patients receiving fluoropyrimidine chemotherapy. Identifying mutations associated with dihydropyrimidine dehydrogenase deficiency may help predict the likelihood of serious side effects and fatalities. This knowledge can be applied to adjust medication doses before starting treatment, thus reducing the occurrence of these critical outcomes. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1186/s12885-024-12981-5.

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Current status and future outlooks on therapeutic drug monitoring of fluorouracil

Cited by 4 publications

References 193 publications

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

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

Current colorectal cancer chemotherapy dosing limitations and novel assessments to personalize treatments

Pharmacogenetics of DPYD and treatment-related mortality on fluoropyrimidine chemotherapy for cancer patients: a meta-analysis and trial sequential analysis

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