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

doi:10.1002/jps.23547

Journal of Pharmaceutical Sciences

Volume 102, Issue 6, June 2013, Pages 2056-2067

https://doi.org/10.1002/jps.23547 Get rights and content

ABSTRACT

We developed a pharmacokinetic/pharmacodynamic (PK/PD) model with the value of the plasma ratio of dihydrouracil (UH2)/uracil (Ura), which is a possible surrogate biomarker of hepatic dihydropyrimidine dehydrogenase activity, determined before 5-fluorouracil (5-FU) treatment to simulate the growth of tumors after 5-FU treatment in rats with colorectal cancer (CRC). In the PK/PD model, the value of the elimination rate constant of 5-FU—k_e—was estimated using the plasma UH2/Ura ratio observed before 5-FU treatment for simulating PKs of 5-FU and tumor growth. The PK/PD model with plasma UH2/Ura ratio effectively captured the features of tumor growth and the anticancer effect of 5-FU treatment, which provided reliable parameter estimates. In addition to an appropriate dosing regimen, pretherapeutic assessment of the UH2/Ura ratio in the plasma of CRC patients and PK/PD analysis with the plasma UH2/Ura ratio could enable the development of an optimal therapeutic scheme for each patient. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2056–2067, 2013

Section snippets

INTRODUCTION

5-Fluorouracil (5-FU), an analogue of the natural pyrimidine uracil (Ura), is a widely used anticancer agent for the management of different types of cancers.1., 2., 3. Currently, it is among the most commonly used chemotherapeutic agents for the treatment of colorectal cancer (CRC).⁴ The objective responses of patients to 5-FU treatment increased with an increase in the values of the area under the plasma 5-FU concentration-time curve (AUC).5., 6. However, the optimal method of 5-FU

Materials

5-Fluorouracil, Ura, UH2, bovine serum albumin (BSA), and methylene blue were purchased from Wako Pure Chemical Industries Ltd. (Osaka, Japan). 5-Bromouracil (5-BU), which was used as an internal standard in the liquid chromatography/tandem mass spectrometry (LC–MS) analysis as described below, was obtained from Sigma–Aldrich Company (Steinheim, Germany). DMH and aminoethylisothiouro- nium bromide were purchased from Tokyo Chemical Industry Company, Ltd. (Tokyo, Japan). We obtained

PK Analysis of 5-FU and UH2/Ura Ratio in CRC Rats

The model fitting of the plasma 5-FU concentration profiles using two-compartment analysis after i.v. administration of 20 mg/kg of 5-FU to CRC rats at different times of the day for 1, 3, or 7 days is shown in Figure 3. The model effectively captured the featuresof the plasma 5-FU concentration (r² > 0.99; Fig. 3). The plasma ratio of UH2/Ura determined before the PK experiments and estimation of PK parameters after i.v. administration of 5-FU (20 mg/kg) to CRC rats at different times of the day

DISCUSSION

A vast amount of clinical data show that dosing of 5- FU on the basis of body surface area cannot achieve optimal concentrations of the drug in a high percentage of patients.³² Studies on associations between plasma concentration of 5-FU with toxicity and clinical efficacy have shown that pharmacokinetically guided dose adjustments substantially improve these biological effects.5., 6., 32. Unfortunately, in these dose adjustments, the dose of 5-FU administered in the first cycle is calculated

CONCLUSIONS

In conclusion, we developed the PK/PD model with plasma UH2/Ura ratio determined before 5-FU treatment to simulate the tumor growth after 5-FU treatment. Because pretherapeutic assessment of the plasma ratio of UH2/Ura is a useful predictor of k_e of 5-FU after administration to CRC rats, the value of k_e in the PK/PD model was estimated using observed plasma UH2/Ura ratio for simulating tumor growth before 5-FU treatment. The PK/PD model with plasma UH2/Ura ratio effectively captured the

ACKNOWLEDGMENTS

This study was supported in part by a Grant-in-Aid for Scientific Research (C) (No. 24590223) from MEXT (Ministry of Education, Culture, Sports, Science and Technology).

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Citation Excerpt :
Rats (n = 21) were randomly divided into three groups based on the 5-FU dose. Rats in each group (n = 7) were administered 5, 10, or 20 mg/kg 5-FU solution [10 mg/mL in saline, intravenous (i.v.) bolus] into the external right jugular vein at 13:00 h for 4 days to account for circadian variations in the PK parameters of 5-FU and activity levels of dihydropyrimidine dehydrogenase (DPD), which is the first and a rate-limiting enzyme of 5-FU catabolism (Kobuchi, Kuwano, et al., 2013; Kobuchi et al., 2013a,b). The 5-FU dose was determined based on the clinical doses administered to and blood concentration profiles observed in human patients.
The aim of the present study was to develop a simple pharmacokinetic–pharmacodynamic (PK–PD) model in rats that could predict the onset and degree of erythropenia, a severely toxic side effect that severely limits the use of the anticancer agent 5-fluorouracil (5-FU).
Total erythrocyte counts, hemoglobin (Hb) concentrations, and hematocrit (Hct) levels were measured in rats following the intravenous bolus administration of 5-FU for 4 days in order to obtain data for an analysis of the PK–PD model. Our PK–PD model consisted of a two-compartment PK model, with two compartments for the PD model and nine structural PK–PD model parameters.
After the intravenous bolus administration of 5, 10, or 20 mg/kg of 5-FU to rats, absolute erythrocyte counts, Hb concentrations, and Hct levels transiently decreased, reached minimum levels on Days 7–14, and then returned to baseline levels. The nadir values (C_nadir) for rats treated with 5, 10, or 20 mg/kg of 5-FU were significantly decreased to approximately 79.4, 76.3, or 46.5% of the baseline value (C_baseline) in erythrocyte counts, 86.3, 83.3, or 45.7% of C_baseline in Hb concentrations, 88.6, 85.5, or 47.1% of C_baseline in Hct levels, respectively. The PK–PD model effectively captured the features of erythropenia and C_nadir after 5-FU chemotherapy. This PK–PD model was successfully used to characterize the learner relationship between the area under the plasma 5-FU concentration-time curve (AUC_0 − ∞) following the intravenous bolus administration of 5-FU and the C_nadir in erythrocyte counts, Hb concentrations, and Hct levels after the 5-FU treatment.
The results of the present study suggest that the administration of a pharmacokinetically modified dose of 5-FU could minimize the C_nadir in erythrocyte counts, Hb concentrations, and Hct levels following the administration of 5-FU. The PK–PD model and simulation represent valuable approaches for quantifying and predicting erythropenia as well as determining individual doses and the time at which the subsequent course of the treatment should start.
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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

ABSTRACT

Section snippets

INTRODUCTION

Materials

PK Analysis of 5-FU and UH2/Ura Ratio in CRC Rats

DISCUSSION

CONCLUSIONS

ACKNOWLEDGMENTS

Semin Oncol

J Pharm Sci

Cancer Lett

J Pharm Sci.

J Pharm Sci

Pathol Biol

Gastroenterology

BiochemPharmacol

Cancer Lett

J Pharm Sci

Gastroenterology

Capecitabineversus classical cyclophosphamide, methotrexate, and fluorouracilas first-line chemotherapy for advanced breast cancer.J

Clin Oncol

Why has induction chemotherapy for advancedhead and neck cancer become a United States communitystandard of practice?

J Clin Oncol

Disease managementconsiderations: Disease management considerations

Drugs

Long-term weekly treatment of colorectalmetastatic cancer with fluorouracil and leucovorin: Resultsof a multicentric prospective trial of fluorouracil dosageoptimization by pharmacokinetic monitoring in 152 patients

J Clin Oncol

Relationship between fluorouracilsystemic exposure and tumor response and patientsurvival

J Clin Oncol

Pharmacokineticallyguided dose adjustment of 5-fluorouracil: A rationalapproach to improving therapeutic outcomes

J Natl CancerInst

Clinical impact of pharmacokinetically-guideddose adaptation of 5-fluorouracil: Results from a multicentricrandomized trial in patients with locally advanced head andneck carcinomas

Clin Cancer Res

Role of body surfacearea in dosing of investigational anticancer agents in adults,1991–2001

J Natl Cancer Inst

Pharmacokineticvariability of anticancer agents

Nat Rev Cancer

Individualfluorouracil dose adjustment based on pharmacokineticfollow-up compared with conventional dosage: Resultsof a multicenter randomized trial of patients with metastaticcolorectal cancer

J Clin Oncol