Pharmacokinetic/Pharmacodynamic Modeling of 5-Fluorouracil by Using a Biomarker to Predict Tumor Growth in a Rat Model of Colorectal Cancer

Kobuchi, Shinji; Ito, Yoshiaki; Okada, Kunihide; Imoto, Kazuki; Kuwano, Shota; Takada, Kanji

doi:10.1002/jps.23547

Cited by 12 publications

(5 citation statements)

References 33 publications

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“…The parameter estimates are shown in Table 1 and simulated concentration-time curves for compartments 1 and 2 are shown in Fig 2 . From the result of parameter estimation, the estimated volume of the central compartment is smaller than that of the peripheral compartment, which agrees with the estimation results shown in the previous PK/PD study [ 20 ]. The elimination phase of the peripheral compartment is slower than that of the central compartment.…”

Section: Resultssupporting

confidence: 90%

“…In recent years, researchers have shown great interest in employing PK/PD models for the prediction of tumor responses to 5-FU. Several conventional PK/PD models in the context of 5-FU treatment have been proposed, in which the transit compartment model is employed to describe the progressive effect on damaged tumor cells [ 20 – 22 ]. Although researchers have gained desirable analysis outcomes through the PK/PD models, the physiological effects under tumor treatment are barely captured.…”

Section: Introductionmentioning

confidence: 99%

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Computational analysis of 5-fluorouracil anti-tumor activity in colon cancer using a mechanistic pharmacokinetic/pharmacodynamic model

Almasan

Gurkan-Cavusoglu

2022

PLoS Comput Biol

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5-Fluorouracil (5-FU) is a standard chemotherapeutic agent to treat solid cancers such as breast, colon, head, and neck. Computational modeling plays an essential role in predicting the outcome of chemotherapy and developing optimal dosing strategies. We developed an integrated mechanistic pharmacokinetics/pharmacodynamics (PK/PD) model examining the influence of 5-FU, as an S-phase specific double-strand break (DSB)-inducing agent, on tumor proliferation. The proposed mechanistic PK/PD model simulates the dynamics of critical intermediate components and provides the accurate tumor response prediction. The integrated model is composed of PK, cellular, and tumor growth inhibition (TGI) sub-models, quantitatively capturing the essential drug-related physiological processes. In the cellular model, thymidylate synthase (TS) inhibition, resultant deoxynucleoside triphosphate (dNTP) pool imbalance, and DSB induction are considered, as well as 5-FU incorporation into RNA and DNA. The amount of 5-FU anabolites and DSBs were modeled to drive the kinetics of the pharmacological tumor response. Model parameters were estimated by fitting to literature data. Our simulation results successfully describe the kinetics of the intermediates regulating the 5-FU cytotoxic events and the pattern of tumor suppression. The comprehensive model simulated the tumor volume change under various dose regimens, and its generalizability was attested by comparing it with literature data. The potential causes of the tumor resistance to 5-FU are also investigated through Monte Carlo analysis. The simulation of various dosage regimens helps quantify the relationship between treatment protocols and chemotherapy potency, which will lead to the development of efficacy optimization.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Computational analysis of 5-fluorouracil anti-tumor activity in colon cancer using a mechanistic pharmacokinetic/pharmacodynamic model

Almasan

Gurkan-Cavusoglu

2022

PLoS Comput Biol

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“…It was reported previously that activated DPD levels in the liver would be induced by CRC and could be evaluated by the measurement of the plasma ratio of UH2/Ura, which is a possible surrogate biomarker of hepatic DPD activity in CRC rats . Moreover, 5‐FU PK and PD studies were conducted using DPD circadian variation in CRC rats and a pharmacokinetic‐pharmacodynamic (PK‐PD) model was developed with the value of the plasma ratio of UH2/Ura determined before 5‐FU treatment, to simulate tumor growth in rats with CRC after 5‐FU treatment . Our observations confirmed the usefulness of the subcutaneous injection of DMH for inducing CRC in rats for the purposes of investigating a correlation between the ratio of UH2/Ura in plasma and hepatic DPD activity after repeated 5‐FU treatment of CRC.…”

Section: Discussionmentioning

confidence: 99%

A predictive biomarker for altered 5‐fluorouracil pharmacokinetics following repeated administration in a rat model of colorectal cancer

Kobuchi

Kuwano

Imoto

et al. 2013

Biopharm & Drug Disp

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The relationship between the plasma ratio of dihydrouracil/uracil (UH2/Ura) and hepatic dihydropyrimidine dehydrogenase (DPD) activity after repeated 5-fluorouracil (5-FU) treatment in rats with colorectal cancer (CRC) was investigated. Repeated intravenous 5-FU bolus injections resulted in a significant decrease in the total clearance (CLtot ) and an increased area under the curve (AUC0-∞ ) in CRC rats. Furthermore, the hepatic DPD levels and the plasma ratio of UH2/Ura decreased significantly and lost their circadian rhythms in CRC rats treated repeatedly with 5-FU, although significant circadian variation in the two parameters was observed in the control CRC rats. Moreover, a significant correlation was found between the plasma ratio of UH2/Ura and hepatic DPD activity in CRC rats untreated and treated with single or repeated 5-FU administration (r(2) = 0.865, p < 0.01). The ratio of UH2/Ura in plasma could be a predictive biomarker of the suppression of hepatic DPD levels during repeated 5-FU-based treatment. Furthermore, by plotting the observed pharmacokinetic parameters of 5-FU against hepatic DPD activity levels predicted by the ratio of UH2/Ura in plasma, AUC0-∞ , CLtot and half-life (t1/2 ) were closely linked to predicted hepatic DPD activity levels. These observations suggest that the factor that significantly influences the AUC0-∞ , CLtot and t1/2 of 5-FU after single or repeated administration of 5-FU is the hepatic DPD activity and it could be assessed by the ratio of UH2/Ura in plasma.

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“…5,6-Dihydrouracil (UH2) is a metabolic product of uracil by dihydropyrimidine dehydrogenase (DPD). The UH2/uracil ratio is a marker of DPD activity and may reflect the response of cancer patients to 5-fluorouracil chemotherapy (43). However, the relationship between a decrease in UH2 and CRF still requires to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Serum metabonomics as a diagnostic approach for cancer‑related fatigue

Wang

Zhao

et al. 2022

Exp Ther Med

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In the present study, differences in metabolic pat hways between patients with and without cancer-related fatigue (CRF) were examined to identify metabolic serum biomarkers of CRF. In this preliminary study, metabolic profiling was applied to analyze the serum samples from 14 patients with CRF and 11 non-CRF individuals (non-fatigue cancer survivors) by ultra-performance liquid chromatography coupled with mass spectrometry. Orthogonal partial least-squares discriminant analysis was adopted to evaluate the differences between the CRF and non-CRF groups. The CRF group was characterized by increases in phosphatidylethanolamine (PE; 18:0/0:0), LysoPE (0:0/20:4 and 0:0/16:0), lysophosphatidylcholine (LysoPC; 20:4, 22:4 and 16:0) and LysoPC/PC, phosphatidylserine (21:0/0:0), glycerophosphocholine and N-docosahexaenoyl γ-aminobutyric acid. Furthermore, decreases in anandamide, uric acid, dihydrouracil, LysoPE (0:0/22:5), 2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman, 19(R)hydroxy-prostaglandin F1α, N-(3α,12α-dihydroxy-5βcholan-24-oyl)-glycine, ketoleucine, indoxyl sulfate, α-N-phenylacetyl-L-glutamine and 1-linoleoyl-glycerophosphocholine were detected. These data indicate a possible disturbance in the metabolism of phospholipids and adjustments in the endocannabinoid system. The metabonomic approach may be helpful to determine the pathophysiological mechanisms of CRF and the identification of potential biomarkers for the accurate diagnosis of CRF. All clinical data were obtained from the 'Research on the efficacy of traditional Chinese medicine comprehensive intervention in cancer-related fatigue' (TCM-CRF) project. Medical Ethical Approval for TCM-CRF was approved by the Chinese Ethics Committee of Registering Clinical Trials. The approval number for the TCM-CRF study was ChiECRCT-2013038, and the TCM-CRF study was completed.

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Pharmacokinetic/Pharmacodynamic Modeling of 5-Fluorouracil by Using a Biomarker to Predict Tumor Growth in a Rat Model of Colorectal Cancer

Cited by 12 publications

References 33 publications

Computational analysis of 5-fluorouracil anti-tumor activity in colon cancer using a mechanistic pharmacokinetic/pharmacodynamic model

Computational analysis of 5-fluorouracil anti-tumor activity in colon cancer using a mechanistic pharmacokinetic/pharmacodynamic model

A predictive biomarker for altered 5‐fluorouracil pharmacokinetics following repeated administration in a rat model of colorectal cancer

Serum metabonomics as a diagnostic approach for cancer‑related fatigue

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