Pharmacokinetic-toxicodynamic Modeling to Elucidate the Involvement of Dorsal Root Ganglion Neuron in Oxaliplatin-induced Peripheral Neuropathy.

BACKGROUND/AIM: Oxaliplatin (L-OHP)-induced peripheral neuropathy (OIPN) limits L-OHP dosage due to nerve cell damage in the dorsal root ganglion (DRG) caused by platinum (Pt). Despite various recommended approaches for OIPN management, no effective approach has been established. The aim of this study was to evaluate Pt distribution into DRG after repeat administrations of L-OHP in rats and to develop a pharmacokinetic-toxicodynamic (PK-TD) model using Pt concentrations in DRG to predict neuropathy severity. MATERIALS AND METHODS: Male Wistar rats were administered L-OHP (3, 5, or 8 mg/kg i.v.) once weekly. Blood and DRG samples were collected following L-OHP administration. For toxicodynamic (TD) study, OIPN was evaluated using the von Frey test. Plasma and DRG Pt concentrations and thresholds values in von Frey test were used for PK-TD modeling using Phoenix WinNonlin® version 8.3 software. RESULTS: Pt concentration in the DRG increased with repeated administration of L-OHP in a dose-dependent manner, indicating Pt accumulation in DRG following multiple administrations. The PK-TD model, consisting of an indirect response model and a transit compartment model with the DRG compartment, adequately described the temporal changes in OIPN with reliable TD parameters (≤36.4% with coefficient of variation). The maximum drug inhibition model could be employed to establish a quantitative correlation between the Pt content present in the DRG and the toxic potency resulting in OIPN. CONCLUSION: The utility of the PK-TD model for predicting neuropathy outcomes was established, suggesting that models composed of the DRG compartment contribute to determining an optimal dosing strategy for reducing OIPN.

Translational PK-PD/TD modeling of antitumor effects and peripheral neuropathy in gemcitabine and nab-paclitaxel chemotherapy from xenograft mice to patients for optimal dose and schedule.

PURPOSE: Gemcitabine and nab-paclitaxel (GnP) treatment, the standard first-line chemotherapy for unresectable pancreatic cancer, often causes peripheral neuropathy (PN). To develop alternative dosing strategies to avoid severe PN, understanding the relationship between pharmacokinetics (PK) and pharmacodynamics/toxicodynamics (PD/TD) is necessary. We established a PK-PD/TD model of GnP treatment to develop an optimal dose schedule. METHODS: A mouse xenograft model of human pancreatic cancer was generated to measure drug concentrations in the plasma and tumor, antitumor effects, and PN after GnP treatment. The Simeoni tumor growth inhibition model with tumor concentrations and empirical indirect response models were used for the PD and TD models, respectively. Clinical outcomes were predicted with reported population estimates of PK parameters in cancer patients. RESULTS: The PK-PD/TD model simultaneously described the observed tumor volume and paw withdrawal frequency in the von Frey test. For the standard GnP regimen, the model predicted clinical overall response (75.1%), which was overestimated compared to that in a recent phase II study (42.1%) but lower than the observed disease control rate (96.5%). Model simulation showed that dose reduction to less than 40% GnP dose was not effective; a change of dose schedule from every week for 3 weeks to every 2 weeks was a more favorable approach than dose reduction to 60% every week. CONCLUSION: The PK-PD/TD model-based translational approach provides a guide for optimal dose determination to avoid severe PN while maintaining antitumor effects during GnP chemotherapy. Further research is needed to enhance its applicability and potential for combination chemotherapy regimens.

Pharmacokinetic evaluation of oxaliplatin combined with S-1 (SOX) chemotherapy in a rat model of colorectal cancer with acute kidney injury: predictive renal biomarkers for dose optimisation.

Dose adjustment based on renal function is essential in S-1, which contains the 5­fluorouracil prodrug tegafur, and platinum-based agent oxaliplatin (SOX) combination chemotherapy for colorectal cancer in patients with chronic kidney disease. However, limited evidence on dose adjustment in acute kidney injury (AKI) and challenges in determining dosing strategies. This study investigated the pharmacokinetics of SOX chemotherapy and renal biomarkers in rats.AKI was prepared by renal ischaemia-reperfusion injury in 1,2-dimethylhydrazine-induced colorectal cancer model rats. Serum creatinine (sCr) levels were determined as a renal biomarker. After administration of S-1 (2 mg/kg tegafur) and oxaliplatin (5 mg/kg), drug concentrations of tegafur, 5-FU, and platinum were measured in the plasma and tumours.No alterations in the area under the plasma concentration-time curve (AUC0-24h) values of 5-fluorouracil were observed between control and AKI model rats. The tumour concentrations of 5-fluorouracil in the mild and severe AKI groups were significantly lower than control group. The AUC0-24h for platinum increased with AKI severity. Notably, population pharmacokinetic analysis identified sCr as a covariate in platinum distribution after SOX chemotherapy.To optimise dose adjustment of SOX chemotherapy in patients with AKI, sCr may be a key factor in determining the appropriate dose.

Mobilization of Circulating Tumor Cells after Short- and Long-Term FOLFIRINOX and GEM/nab-PTX Chemotherapy in Xenograft Mouse Models of Human Pancreatic Cancer.

Mobilization of CTCs after various types of therapy, such as radiation therapy, has been reported, but systematic study of CTCs after chemotherapy remained quite limited. In this study, we sequentially examined CTC numbers after single-dose and repetitive-dose chemotherapy, including FORFIRINOX (FFX) and Gemcitabine and nab-Paclitaxel (GnP) using two pancreatic cancer xenograft models. CTC was detected by the immunocytology-based microfluidic platform. We further examined the dynamic change in the histology of primary tumor tissues during chemotherapy. We confirmed a transient increase in CTCs 1-2 weeks after single-dose and repetitive-dose of FFX/GnP chemotherapy. Histological examination of the primary tumors revealed that the peak period of CTC at 1-2 weeks after chemotherapy corresponded to the maximal destructive phase consisting of cell cycle arrest, apoptosis of tumor cells, and blood vessel destruction without secondary reparative tissue reactions and regeneration of tumor cells. These findings indicate that mobilization of CTCs early after chemotherapy is mediated by the shedding of degenerated tumor cells into the disrupted blood vessels driven by the pure destructive histological changes in primary tumor tissues. These results suggest that sequential CTC monitoring during chemotherapy can be a useful liquid biopsy diagnostic tool to predict tumor chemosensitivity and resistance in preclinical and clinical settings.

Children's Diet and Nutrition in the Aftermath of the Torrential Rain Disaster in Western Japan: An Evaluation of Support Activities by Dietitians to Alleviate Mothers' Anxieties.

OBJECTIVE: The purpose of this study was to clarify whether the support activities of dietitians during disasters were able to address the problems faced by mothers about their children's diet and nutrition. METHODS: Dietitians (7 in total) and mothers (8) were selected by the snowball sampling method. Semi-structured interviews were used to conduct focus group interviews about children's diet and nutrition. Verbatim data were generated, and an inductively qualitative descriptive analysis was conducted. RESULTS: Six categories were generated for each group. Dietitians responded to problems that mothers had regarding their children's diet and nutrition via 2 activities: [dealing with allergy food shortages] and [school lunch support]. CONCLUSION: It is important for dietitians to recommend stockpiling allergy-friendly foods to accommodate children with allergies and achieve early resumption of school lunches to meet children's nutritional needs.

A Pharmacokinetic-Pharmacodynamic Model Predicts Uracil-tegafur Effect on Tumor Shrinkage and Myelosuppression in a Colorectal Cancer Rat Model.

BACKGROUND/AIM: Oral 5-fluorouracil (5-FU)-based prodrugs, used in cancer chemotherapeutic regimens, exhibit large inter- and intra-patient variability in plasma 5-FU concentrations, contributing to treatment failure. Although dosage determination criteria according to plasma drug concentrations are required, the relationship between pharmacokinetics and drug response after multiple oral 5-FU derivative administrations remain unknown. MATERIALS AND METHODS: We evaluated the pharmacokinetics and pharmacodynamics/toxicodynamics of uracil-tegafur (UFT) after multiple administrations in colorectal cancer (CRC) model rats, and applied a pharmacometric approach to describe the time-course alterations of plasma 5-FU concentrations and tumor shrinkage. CRC was induced in rats using 1,2-dimethylhydrazine and dextran sulfate sodium. UFT (30 mg/kg as tegafur) was administered to CRC rats for 14 days. RESULTS: Plasma 5-FU exposure levels increased with the dosing time, and large variations were observed in tumor 5-FU concentrations (32.0-125.8% with coefficient of variation). Although severe hematological toxicities were not observed, a weak correlation was observed between blood platelet count and the plasma 5-FU concentration (r=0.439, p=0.176). A simple pharmacokinetic-pharmacodynamic model was developed comprising of a small number of parameters and successfully describing plasma 5-FU levels and tumor shrinkage after multiple UFT administrations. CONCLUSION: A pharmacometric model approach can help establish the dose-determination criteria based on plasma 5-FU concentration of UFT-based regimens, and contribute to improvement of clinical outcomes.

Predictive marker for exposure-driven haematological toxicity of tegafur-uracil and proposed modified-dosage regimen by pharmacometric approach in rats.

Myelosuppression is a dose-limiting toxicity of uracil-tegafur (UFT), which contains uracil and the 5­fluorouracil prodrug tegafur, and inhibits the continuation of chemotherapy, causing treatment failure. A proper dosing strategy to avoid severe myelosuppression-induced discontinuation of chemotherapy is required.Plasma drug concentrations were determined in rats after single oral UFT administration of 15, 30, or 60 mg/kg. Blood cell counts were also measured after oral UFT administration for 5 days. Pharmacokinetic-toxicodynamic (PK-TD) modelling and simulation were performed to describe the time-course alterations in the blood cell counts.Severe neutropenia was observed in rats treated with 60 mg/kg UFT on day 7. A significant decrease in neutrophil counts from baseline levels prior to UFT administration was observed on day 3, whereas leukocyte and lymphocyte counts decreased on day 7. The semi-physiological PK-TD model successfully captured alterations in neutrophil counts after UFT administration, whereas the model could not well describe the platelet, leukocyte, and lymphocyte counts, possibly due to the absence of severe thrombocytopenia, leukocytopenia, and lymphocytopenia, respectively.Neutrophils are sensitive markers for estimating the grade of haematological toxicity of UFT, and a PK-TD model might be an attractive tool for quantitatively evaluating the onset and degree of myelosuppression.

Comparing the pharmacokinetics and organ/tissue distribution of anti-methicillin-resistant Staphylococcus aureus agents using a rat model of sepsis.

Sepsis is a major cause of death, and sepsis-derived physiological changes complicate the understanding of drug distribution in organs/tissues, which determines the efficacy and toxicity of antimicrobial agents. In this study, we evaluated and compared the pharmacokinetics of methicillin-resistant Staphylococcus aureus treatment agents in sepsis with that of vancomycin, arbekacin, linezolid, and daptomycin.Rat models of sepsis were prepared using caecal ligation puncture. The pharmacokinetics of vancomycin, arbekacin, linezolid, and daptomycin were evaluated using their drug concentration profiles in plasma, kidneys, liver, lungs, skin, and muscles after intravenous administration in normal and septic rats.The kidney/plasma concentration ratio was higher in septic rats than in normal rats for vancomycin, arbekacin, and daptomycin but not for linezolid. The increase in the kidney/plasma concentration ratio for vancomycin was time-dependent, indicating an association between sepsis and stasis of vancomycin in the kidneys. In contrast, the distribution of linezolid from the blood to the organs/tissues in septic rats was comparable to that in normal rats.Sepsis-induced nephrotoxicity results in the stasis of vancomycin in the kidney, suggesting that this exacerbates proximal tubular epithelial cell injury. No dose modification of linezolid may be required for patients with sepsis.

Assessment of Drug-drug Interaction and Optimization in Capecitabine and Irinotecan Combination Regimen using a Physiologically Based Pharmacokinetic Model.

Capecitabine and irinotecan (CPT-11) combination regimen (XELIRI) is used for colorectal cancer treatment. Capecitabine is metabolized to 5-fluorouracil (5-FU) by three enzymes, including carboxylesterase (CES). CES can also convert CPT-11 to 7-ethyl-10-hydroxycamptotecin (SN-38). CES is involved in the metabolic activation of both capecitabine and CPT-11, and it is possible that drug-drug interactions occur in XELIRI. Here, a physiologically based pharmacokinetic (PBPK) model was developed to evaluate drug-drug interactions. Capecitabine (180 mg/kg) and CPT-11 (180 mg/m2) were administered to rats, and blood (250 µL) was collected from the jugular vein nine times after administration. Metabolic enzyme activities and Ki values were calculated through in vitro experiments. The plasma concentration of 5-FU in XELIRI was significantly decreased compared to capecitabine monotherapy, and metabolism of capecitabine by CES was inhibited by CPT-11. A PBPK model was developed based on the in vivo and in vitro results. Furthermore, a PBPK model-based simulation was performed with the capecitabin dose ranging from 0 to 1000mol/kg in XELIRI, and it was found that an approximately 1.7-fold dosage of capecitabine was required in XELIRI for comparable 5-FU exposure with capecitabine monotherapy. PBPK model-based simulation will contribute to the optimization of colorectal cancer chemotherapy using XELIRI.

Population Pharmacokinetic Model-Based Evaluation of Intact Oxaliplatin in Rats with Acute Kidney Injury.

Acute kidney injury (AKI) complicates the dosing strategies of oxaliplatin (L-OHP) and the requirement for L-OHP dose reduction in patients with renal failure remains controversial. The objective of this study is to assess the impact of AKI on the pharmacokinetics (PK) of intact L-OHP and simulate the relationship between the degree of renal function and intact L-OHP exposures using a population PK model. Intact L-OHP concentrations in plasma and urine after L-OHP administration were measured in mild and severe AKI models established in rats through renal ischemia-reperfusion. Population PK modeling and simulation were performed. There were no differences among rats in the area under the plasma concentration-time curve of intact L-OHP after intravenous L-OHP administrations. Nevertheless, the amount of L-OHP excretion after administration of 8 mg/kg L-OHP in mild and severe renal dysfunction rats was 63.5% and 37.7%, respectively, and strong correlations were observed between biochemical renal function markers and clearance of intact L-OHP. The population PK model simulated well the observed levels of intact L-OHP in AKI model rats. The population PK model-based simulation suggests that dose reduction is unnecessary for patients with mild to moderate AKI.

Prolonged Maternal and Child Health, Food and Nutrition Problems after the Kumamoto Earthquake: Semantic Network Analysis of Interviews with Dietitians.

Infants need sufficient nutrients even during disasters. Only qualitative descriptive analysis has been reported regarding nutritional problems of mothers and children after the Kumamoto earthquake, and non-subjective analysis is required. This study examined issues concerning maternal and child health, food and nutrition after the Kumamoto earthquake using automatic computer quantitative analysis from focus group interviews (FGIs). Study participants (n = 13) consisted of dietitians in charge of nutrition assistance of infants in affected areas. The content of the interviews was converted into text, nouns were extracted, and co-occurrence network diagram analysis was performed. In the severely damaged area, there were hygienic problems not only in the acute phase but also in the mid-to-long-term phase. "Allergy" was extracted in the surrounding area in the acute and the mid-to-long-term phase, but not in the severely damaged area as the acute phase issue. In the surrounding area, problems have shifted to health and the quality of diet in the mid-to-long-term phase. This objective analysis suggested that dietary problems for mothers and children after disaster occurred also in the mid-to-long-term phase. It will be necessary to combine the overall trends obtained in this study with the results of qualitative descriptive analysis.

A Physiologically Based Pharmacokinetic-Pharmacodynamic Model for Capecitabine in Colorectal Cancer Rats: Simulation of Antitumor Efficacy at Various Administration Schedules.

BACKGROUND AND OBJECTIVES: Capecitabine is an oral prodrug of 5-fluorouracil and is widely used for colorectal cancer (CRC) treatment. However, knowledge of its antitumor efficacy after modification of the dosing schedule is insufficient. The aim of this study was to predict the antitumor efficacy of capecitabine using a physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model based on metabolic enzyme activities. METHODS: CRC model rats were administrated 180 mg/kg of capecitabine for 2 weeks. Blood samples were collected at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, and 8 h following capecitabine administration. Plasma concentrations of capecitabine and its metabolites were measured on days 1, 7, and 14. Metabolic enzyme activities were determined in vitro using the liver and small intestine of the CRC model rats. A PBPK-PD model was developed based on metabolic enzyme activities. The antitumor efficacy of capecitabine after regimen modification was simulated using the PBPK-PD model. RESULTS: Capecitabine antitumor efficacy was dose-dependent. A dose of > 500 µmol/kg was needed to inhibit tumor growth. After capecitabine regimen modification, a 1-week postponement of capecitabine administration was more efficacious than a reduction in the dosage to 80%. CONCLUSIONS: The PBPK-PD model could simulate the antitumor efficacy at various capecitabine administration schedules. PBPK-PD models can contribute to the development of an appropriate CRC chemotherapy regimen with capecitabine.

Comparison of In Vivo Transportability of Anti-Methicillin-Resistant Staphylococcus aureus (MRSA) Agents Into Intracellular and Extracellular Tissue Spaces in Rats.

The pathogenic bacterium Staphylococcus aureus can penetrate host cells. However, intracellular S. aureus is not considered during antimicrobial agent selection in clinical chemotherapy because of the lack of information about drug transportability into cells in vivo. We focused on agents used to treat methicillin-resistant S. aureus (MRSA) (vancomycin, arbekacin, linezolid, and daptomycin) and indirectly assessed the drug levels in intracellular compartment using plasma, tissue homogenates, and interstitial fluid (ISF) samples from the skin of rats using the microneedle array technique. Lower drug levels were observed in the ISF than in the plasma for daptomycin but extracellular and intracellular drug levels were comparable. In contrast, vancomycin, arbekacin, and linezolid showed higher concentrations in the ISF than in the plasma. Intracellular transport was estimated only for arbekacin. Stasis of vancomycin in the ISF was also observed. These results suggest that both low vancomycin exposure against intracellular S. aureus infection and long-term subinhibitory drug levels in the ISF contribute to the failure of treatment and emergence of antibiotic resistance. Based on its pharmacokinetic characteristics in niche extravascular tissue spaces, arbekacin may be suitable for achieving sufficient clinical outcomes for MRSA infection because the drug is widely distributed in extracellular and intracellular compartments.

Application of Pharmacometrics of 5-Fluorouracil to Personalized Medicine: A Tool for Predicting Pharmacokinetic-Pharmacodynamic/Toxicodynamic Responses.

Recently, therapeutic drug monitoring of 5-fluorouracil (5-FU), the key chemotherapeutic drug for colorectal cancer, has been applied in daily clinical practice and has contributed towards improving clinical outcomes. However, current dose modifications are based only on values of the area under the plasma concentration-time profile, which are simply calculated from plasma 5-FU concentrations and infusion periods. When dose-limiting toxicities occur, the dosing is empirically reduced or discontinued, leading to treatment failure. To prevent this predictable failure and obtain better clinical outcomes, rational dosage-based strategies are required for 5-FU. Combining therapeutic drug monitoring with a mathematical approach using a pharmacokinetic- pharmacodynamic/toxicodynamic model is expected to help simulate time-course profiles of the efficacy of drugs and the degree of toxicity, thereby contributing towards dose setting for individual patients. Therefore, to facilitate pharmacometric modelling and simulation techniques for optimising current oncology therapies, this review focuses on pharmacometrics approaches for personalizing 5-FU-based chemotherapy.

Cytology-based Detection of Circulating Tumour Cells in Human Pancreatic Cancer Xenograft Models With KRAS Mutation.

BACKGROUND/AIM: To examine the dynamics of circulating tumour cells (CTCs) in pancreatic cancer (PC), new mouse CTC models from human PC xenografts were developed. MATERIALS AND METHODS: Orthotopic (pancreas) and heterotopic (subcutaneous) transplantation models using GFP-tagged SUIT-2 PC cells were prepared. Using a cytology-based CTC detection platform, CTCs and metastasis were compared. RESULTS: The two types of orthotopic models, including the surgical transplantation model and the intraperitoneal injection model, showed a similar pattern of initial pancreatic tumour formation and subsequent development of peritoneal and hematogenous lung metastases. In the heterotopic model, only hematogenous lung metastasis was observed, and the number of CTCs and lung metastases was higher than that of the orthotopic model. Furthermore, KRAS mutation (G12D) was detected in CTCs. CONCLUSION: These orthotopic and heterotopic models clearly differ in terms of the pattern of metastasis and CTCs and therefore, would be useful PC models to investigate the effect of drug-therapy on CTCs and the role of KRAS mutation.

Effect of intact oxaliplatin in plasma on a cold allodynia after multiple administrations in colorectal cancer model rats.

BACKGROUND: Oxaliplatin (L-OHP)-induced acute neuropathy is a major factor for influencing treatment compliance in patients receiving chemotherapy for colorectal cancer (CRC). Acute neuropathy is caused by the intact L-OHP affecting the function of transient receptor potential vanilloid 1 (TRPV1) channel. In this study, the effectiveness of the detection of the intact L-OHP and the association with the severity of L-OHP-induced acute neuropathy were investigated using a rat model of CRC. METHODS: Wistar male rats were prepared as models of CRC by using 1,2-dimethylhydrazine (DMH) and dextran sulfate. Intravenous L-OHP was administered (weekly) to CRC rats for 4 weeks, at doses of 3, 5, or 8 mg/kg, respectively. Pharmacokinetic and tumor distribution profiles of animals with intact L-OHP were observed on days 1 and 22. Cold allodynia was determined as a read-out of acute neuropathy using the acetone test over the 4 weeks. RESULTS: The mean AUC0-∞ values for the intact L-OHP were increased dose-dependently at the three doses. The accumulation of intact L-OHP was confirmed following an increase in L-OHP concentration on day 22. Acute neuropathy was observed from day 2 at all doses and the withdrawal response correlated with AUC (R2 =0.9816). CONCLUSIONS: To prevent the onset of L-OHP-induced acute neuropathy, the timely detection of the intact L-OHP is important. These findings could be a basis of the establishment a pharmacokinetic and toxicodynamic model to aid the planning of therapy cycle completion for CRC.

A validated LC-MS/MS method for the low-level determination of pemafibrate, a novel SPPARMα, in plasma.

Background: Pemafibrate, a novel selective peroxisome proliferator-activated receptor-α modulator, is prescribed for patients with dyslipidemia. To investigate other potential nonlipid-related effects of pemafibrate, the sensitive and rapid quantitation method for pemafibrate was required. Results: The developed LC-MS/MS assay method exhibited excellent accuracy, precision, sensitivity, stability, no matrix effect and high recovery. The LOQ (0.05 ng/ml) and run time (6.0 min) were superior to previous reports. The calibration curve showed good linearity over the wide concentration range (0.05-100.00 ng/ml). This validated method was successfully applied in a rat pharmacokinetic study using lower doses (0.02 or 0.10 mg/kg) than have been previously reported. Conclusion: This method can support gathering data for the evaluation of pemafibrate in future studies.

Pharmacokinetics of Macrolide Antibiotics and Transport into the Interstitial Fluid: Comparison among Erythromycin, Clarithromycin, and Azithromycin.

Recent research has found higher levels and longer total exposure of azithromycin, a macrolide antibiotic agent, in the interstitial fluid of the skin than in the plasma. This unique distribution is expected to contribute to its antimicrobial activity at the primary infection site. However, it remains unclear whether this characteristic distribution in the extracellular tissue space is common to macrolide antibiotics or if it is azithromycin-specific, with most macrolides largely localized intracellularly. In this study, we investigated pharmacokinetic characteristics of erythromycin and clarithromycin in the interstitial fluid of the skin of rats after intravenous drug administration, and compared the results with our previously reported results on azithromycin. Interstitial fluid samples were directly collected from a pore on the skin using a dissolving microneedle array. We found that the total macrolide concentrations in the interstitial fluid were significantly different among three macrolides. The rank order of the interstitial fluid-plasma concentration ratio was azithromycin (3.8 to 4.9) > clarithromycin (1.2 to 1.5) > erythromycin (0.27 to 0.39), and this ratio was stable after dosing, whereas higher drug levels in the skin tissue than in the plasma were observed for all three macrolides. Our results suggest that lower erythromycin concentrations in the interstitial fluid than in the plasma contributes to the emergence of bacterial resistance in the extracellular tissue space. Monitoring of total macrolide concentrations in interstitial fluid may provide valuable information regarding antimicrobial effects and the emergence of bacterial resistance for the development of an appropriate pharmacokinetics-pharmacodynamics-based dosing strategy.

Population Pharmacokinetic Model-Based Evaluation of Circadian Variations in Plasma 5-Fluorouracil Concentrations During Long-Term Infusion in Rats: A Comparison With Oral Anticancer Prodrugs.

Circadian fluctuations in the plasma concentration of 5-fluorouracil impede the accurate estimation of target therapeutic concentrations in the long-term infusion or oral 5-fluorouracil-based prodrug regimen. We evaluated the circadian patterns of plasma 5-fluorouracil concentrations in rats using population pharmacokinetic model. Rats were divided into 2 groups, and a continuous infusion (50 mg/m2/h) for 48 h was initiated with or without a bolus injection of 60 mg/kg 5-fluorouracil. In the group not administered a loading dose, significant circadian variation of plasma 5-fluorouracil concentration was observed. In contrast, in the loading dose group, this circadian variation disappeared. Additionally, decreased hepatic dihydropyrimidine dehydrogenase activity was observed. Population model analysis revealed that the concentrations of 5-fluorouracil followed a 24-h cosine circadian curve, representing an overall 1.8-fold increase from a nadir to a peak, with a relative amplitude (% of mesor) of 28%. The circadian 5-fluorouracil clearance pattern in the infusion-regimen was consistent with previously reported pattern for capecitabine and uracil-tegafur. In the recently modified regimen omitting the bolus injection of 5-fluorouracil, the circadian variations should be considered for blood sampling time points in therapeutic drug monitoring. The chronomodulated chemotherapy using oral prodrug administration could be established based on accumulating evidence in the infusion-regimen.

Assessment of pharmacokinetic variations of capecitabine after multiple administration in rats: a physiologically based pharmacokinetic model.

PURPOSE: Capecitabine is a prodrug of 5-fluorouracil (5-FU) used for the treatment of colorectal cancer, with a two-week course of administration. However, the variance in plasma concentration and metabolic enzyme activities after multiple administration of capecitabine and its metabolites is unknown. The aim of this study was to identify the variance and predict the plasma concentration profile of capecitabine and its metabolites, using metabolic enzyme activities, to develop a more effective and safer medication. METHODS: Rats orally received 180 mg/kg of capecitabine once a day for two weeks. Blood samples were collected nine times, and plasma concentration was measured on day 1, 7, and 14. The liver and small intestine were removed after blood sampling and were used in vitro to evaluate metabolic enzyme activities of carboxylesterase, cytidine deaminase, and thymidine phosphorylase. A physiologically based pharmacokinetic (PBPK) model was developed using in vitro results. RESULTS: Area under the plasma concentration-time curve from 0 h to infinity of 5-FU on day 7 and day 14 was significantly lower than that on day 1. Intrinsic clearance of thymidine phosphorylase in the liver on day 7 and day 14 was 1.4 and 1.3 times lower than that on day 1, respectively. The PBPK model described the observed plasma concentration of capecitabine and its metabolites. CONCLUSION: The decreased plasma concentration of capecitabine was caused by decreased metabolic enzyme activity. Efficacy can be improved by dose adjustment of capecitabine based on metabolic enzyme activities, using the PBPK model.