Evaluation of 5-Fluorouracil Pharmacokinetics in Cancer Patients with a C.1905+1G&gt;A Mutation in DPYD by Means of a Bayesian Limited Sampling Strategy

Kuilenburg, André B. P.; Häusler, Peter; Schalhorn, Andreas; Tanck, Michael W.T.; Proost, Johannes H.; Terborg, C.; Behnke, Detlev; Schwabe, Wolfgang; Jabschinsky, K.; Maring, Jan Gerard

doi:10.1007/bf03257473

Cited by 67 publications

(49 citation statements)

References 41 publications

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“…In the field of oncology, researchers are focusing on the identification of predictive markers to improve the efficacy of 5-FU and decrease the likelihood of severe toxicity, which remain a challenge. 12) Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting step in the catabolism of 5-FU, 13) and approximately 90% of administered 5-FU is metabolized by DPD in the liver.…”

mentioning

confidence: 99%

Pre-therapeutic Assessment of Plasma Dihydrouracil/Uracil Ratio for Predicting the Pharmacokinetic Parameters of 5-Fluorouracil and Tumor Growth in a Rat Model of Colorectal Cancer

Kobuchi

Ito

Okada

et al. 2013

Biological & Pharmaceutical Bulletin

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We investigated the correlation between plasma ratio of dihydrouracil/uracil (UH2/Ura), a possible surrogate biomarker of hepatic dihydropyrimidine dehydrogenase (DPD) activity, and 5-fluorouracil (5-FU) treatment efficacy in rats with colorectal cancer (CRC). 5-FU pharmacokinetic and pharmacodynamic studies were performed using DPD circadian variation in rats with 1,2-dimethylhydrazine-induced CRC. By plotting tumor volume after 5-FU treatment against pre-therapeutic plasma UH2/Ura, we inferred a linear relationship (r 2 =0.988). 5-FU concentration fluctuations induced by DPD activity variation affected tumor volume. In CRC patients receiving proper dosing regimens, plasma UH2/Ura could be an indirect biomarker for predicting 5-FU treatment efficacy, tumor growth, and 5-FU doses.Key words pharmacokinetics; biomarker; dihydropyrimidine dehydrogenase; anti-cancer agent Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality in Western and welldeveloped countries.1) Several environmental factors, including lifestyle, food, and body mass, play important roles in the induction and progression of CRC.2) Generally, surgery is the first-line treatment for patients with early-stage CRC (stage I or II), and it has been reported to afford a positive prognosis.3,4) However, surgery is less effective in patients with more advanced CRC (stage III); furthermore, patients with involvement of the lymph nodes are at a 50% risk of relapse following resection.3,4) Therefore, adjuvant chemotherapy is often prescribed for patients with lymph node involvement in order to reduce the risk of recurrence.5-Fluorouracil (5-FU), an analogue of the natural pyrimidine uracil (Ura), is an anti-cancer agent that is widely used in the management of patients with cancers of the gastrointestinal tract, breast, head, and neck.5-7) At present, 5-FU remains the single, most effective chemotherapeutic agent for the treatment of CRC. 8) Some studies have shown a relationship between systemic plasma levels of 5-FU and treatment efficacy. 9,10) Increased objective responses have been demonstrated when higher 5-FU area under the curve (AUC) values are maintained.9,10) However, the optimal method of using 5-FU remains debatable. Gamelin et al. conducted a randomized, phase III multicentre clinical trial involving 208 patients with metastatic CRC and reported wide pharmacokinetic (PK) variability and a large distribution of the optimal dose of 5-FU to achieve target 5-FU plasma levels.11) To achieve the prescribed target concentration levels, dose increase was required in 68% of the patients. The study investigators concluded that individual 5-FU dose adjustment on the basis of PK monitoring, not body surface area, is needed for an improved objective response rate, a higher survival rate, and fewer grade III/IV toxicities. In the field of oncology, researchers are focusing on the identification of predictive markers to improve the efficacy of 5-FU and decrease the likelihood of severe toxicity, which remain a challeng...

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mentioning

confidence: 99%

Pre-therapeutic Assessment of Plasma Dihydrouracil/Uracil Ratio for Predicting the Pharmacokinetic Parameters of 5-Fluorouracil and Tumor Growth in a Rat Model of Colorectal Cancer

Kobuchi

Ito

Okada

et al. 2013

Biological & Pharmaceutical Bulletin

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“…This means that 4 patients in the group with AUCs below the cutoff need to be above the cutoff to gain an extra patient who will be disease free after 10 years. van Kuilenburg et al 75 have recently reported the use of pharmacokinetic profiling of 5FU in dihydropyrimidine dehyrogenase-deficient patients.…”

Section: -Fluorouracilmentioning

confidence: 99%

Target Concentration Intervention in Oncology

Saleem

Dimeski

Kirkpatrick

et al. 2012

Therapeutic Drug Monitoring

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Therapeutic drug monitoring (TDM) and more recently target concentration intervention (TCI) have been widely used in clinical practice for the optimization of drug treatment. TDM and TCI have been applied most frequently in the cardiovascular, respiratory, neurology, and infectious disease areas because the medications used here have both narrow therapeutic indices and a clear relationship between concentration and effect. However, apart from drugs such as methotrexate and 5-fluorouracil, the clinical application of TDM/TCI in oncology is minimal. An important reason for this is that a therapeutic index for most anticancer agents has not been established. However, in the last 20 years, relationships between plasma drug concentrations and clinical outcome have been defined for various chemotherapeutic agents. Defining concentration-effect relationships is also complicated by the fact that cancer is almost always treated with multiple drugs given in combination making the precise definition of the pharmacodynamics of individual agents difficult. The increase in patients with obesity and also those underweight adds to the complexity of effective oncology treatment. This review describes some of the evidence that supports the use of TDM/TCI in oncology. It is proposed that as more patients previously ineligible for chemotherapy become eligible, TDM/TCI may play a critical role in optimizing chemotherapy outcomes. However, pharmacokinetic-pharmacodynamic research to investigate both therapeutic benefit and feasibility in daily clinical practice is required.

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“…DPD activity is highly variable, influencing the patient's response to 5-FU, which could be due to SNP genetic polymorphism (7)(8)(9)(13)(14)(15)(16)(17)(18). The SNPs of DPD cause enzymatic deficiency from partial (3-5% of the population) to complete loss (0.2% of the population) of enzyme activity (7)(8)(9)(13)(14)(15)(16)(17)(18)(19). More than 40 different DPD alleles have been identified (13)(14)(15)(16)(17)(18)(19).…”

Section: -Fuorouracil (5-fu) Is a Widely Used Anticancermentioning

confidence: 99%

“…The SNPs of DPD cause enzymatic deficiency from partial (3-5% of the population) to complete loss (0.2% of the population) of enzyme activity (7)(8)(9)(13)(14)(15)(16)(17)(18)(19). More than 40 different DPD alleles have been identified (13)(14)(15)(16)(17)(18)(19). To date, the respective frequencies of different SNPs and their effects, especially in China, have not been investigated in detail.…”

Section: -Fuorouracil (5-fu) Is a Widely Used Anticancermentioning

confidence: 99%

Evaluation of Clinical Value of Single Nucleotide Polymorphisms of Dihydropyrimidine Dehydrogenase Gene to Predict 5-Fluorouracil Toxicity in 60 Colorectal Cancer Patients in China

Zhang¹,

Sun²,

Lu³

2013

Int. J. Med. Sci.

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Dihydropyrimidine dehydrogenase (DPD) activity could be affected by single nucleotide polymorphisms (SNPs), resulting in either no effect, partial or complete loss of DPD activity. To evaluate if SNPs of DPD can be used to predict 5-FU toxicity, we evaluated five SNPs of DPD (14G1A, G1156T, G2194A, T85C and T464A) by TaqMan real time PCR in 60 colorectal cancer patients. Clinical data demonstrated that there was higher correlation between DPD activity and toxic effects of 5-FU (p<0.05). Six patients were positive for G2194A detection, which were all heterozygous. Two patients had lower DPD activities (< 3) with higher toxic effects (≥stage III) while one patient was also positive for T85C detection. Ten patients were positive for T85C detection. Two patients were homozygous with lower DPD activities and higher toxic effects. Two patients were positive for the T464A detection, which were heterozygous with lower DPD activity and higher toxic effects and also positive for T85C detection. These data clearly indicated that the T464A and homozygous of the T85C are stronger biomarkers to predict the 5-FU toxicity. Our study significantly indicated that the detection for G2194A, T85C and T464A could predict ~13% of 5-FU severe toxic side effects.

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Evaluation of 5-Fluorouracil Pharmacokinetics in Cancer Patients with a C.1905+1G>A Mutation in DPYD by Means of a Bayesian Limited Sampling Strategy

Cited by 67 publications

References 41 publications

Pre-therapeutic Assessment of Plasma Dihydrouracil/Uracil Ratio for Predicting the Pharmacokinetic Parameters of 5-Fluorouracil and Tumor Growth in a Rat Model of Colorectal Cancer

Pre-therapeutic Assessment of Plasma Dihydrouracil/Uracil Ratio for Predicting the Pharmacokinetic Parameters of 5-Fluorouracil and Tumor Growth in a Rat Model of Colorectal Cancer

Target Concentration Intervention in Oncology

Evaluation of Clinical Value of Single Nucleotide Polymorphisms of Dihydropyrimidine Dehydrogenase Gene to Predict 5-Fluorouracil Toxicity in 60 Colorectal Cancer Patients in China

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