A phase 1b/2, open-label, dose-escalation, and dose-confirmation study of eribulin mesilate in combination with capecitabine.

BACKGROUND: Capecitabine and eribulin are widely used as single agents in metastatic breast cancer (MBC) and have nonoverlapping toxicities. METHODS: In phase 1b (dose escalation), patients with advanced, treatment-refractory, solid tumours received eribulin mesilate intravenously in 21-day cycles according to schedule 1 (day 1) or schedule 2 (days 1, 8) with twice-daily oral capecitabine (1000 mg/m2 days 1-14). In phase 2 (dose confirmation), women with advanced/MBC and ≤3 prior chemotherapies received eribulin mesilate at the maximum tolerated dose (MTD) per the preferred schedule plus capecitabine. Primary objectives were MTD and dose-limiting toxicities (DLTs; phase 1b) and objective response rate (ORR; phase 2). Secondary objectives included progression-free survival (PFS), safety, and pharmacokinetics. RESULTS: DLTs occurred in 4/19 patients (schedule 1) and 2/15 patients (schedule 2). Eribulin pharmacokinetics were dose proportional, irrespective of schedule or capecitabine coadministration. The MTD of eribulin was 1.6 mg/m2 day 1 for schedule 1 and 1.4 mg/m2 days 1 and 8 for schedule 2. ORR in phase 2 (eribulin 1.4 mg/m2 days 1, 8 plus capecitabine) was 43% and median PFS 7.2 months. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and lethargy. CONCLUSIONS: The combination of capecitabine and eribulin showed promising efficacy with manageable tolerability in patients with MBC.

Mining Small Routine Clinical Data: A Population Pharmacokinetic Model and Optimal Sampling Times of Capecitabine and its Metabolites.

PURPOSE: The present study was performed to demonstrate that small amounts of routine clinical data allow to generate valuable knowledge. Concretely, the aims of this research were to build a joint population pharmacokinetic model for capecitabine and three of its metabolites (5-DFUR, 5-FU and 5-FUH2) and to determine optimal sampling times for therapeutic drug monitoring. METHODS: We used data of 7 treatment cycles of capecitabine in patients with metastatic colorectal cancer. The population pharmacokinetic model was built as a multicompartmental model using NONMEM and was internally validated by visual predictive check. Optimal sampling times were estimated using PFIM 4.0 following D-optimality criterion. RESULTS: The final model was a multicompartmental model which represented the sequential transformations from capecitabine to its metabolites 5-DFUR, 5-FU and 5-FUH2 and was correctly validated. The optimal sampling times were 0.546, 0.892, 1.562, 4.736 and 8 hours after the administration of the drug. For its correct implementation in clinical practice, the values were rounded to 0.5, 1, 1.5, 5 and 8 hours after the administration of the drug. CONCLUSIONS: Capecitabine, 5-DFUR, 5-FU and 5-FUH2 can be correctly described by the joint multicompartmental model presented in this work. The aforementioned times are optimal to maximize the information of samples. Useful knowledge can be obtained for clinical practice from small databases.

Association between the pharmacokinetics of capecitabine and the plasma dihydrouracil to uracil ratio in rat: A surrogate biomarker for dihydropyrimidine dehydrogenase activity.

Capecitabine is a 5-fluorouracil (5-FU) derivative that is used widely in the treatment of colorectal cancer. The plasma ratio of dihydrouracil (UH2 ) to uracil (Ura) is expected to gain relevance as an indirect-response biomarker to estimate the activity of dihydropyrimidine dehydrogenase (DPD). The latter is a rate-limiting enzyme in the catabolism of 5-FU in the capecitabine-based regimen. However, the relationship between the pharmacokinetics of capecitabine and the plasma UH2 /Ura ratio is still unknown. This study evaluated the time-course alterations of the plasma UH2 /Ura ratio in rats treated with 180 mg/kg capecitabine. The molar ratio tended to increase within 1.5 h (1.85 ± 0.76 at 1.5 h after administration of capecitabine) and gradually recovered to its initial level (1.00 ± 0.46). The results of the current study suggest that the plasma UH2 /Ura ratio temporarily increases following administration of capecitabine, possibly related to the DPD activity levels. The plasma UH2 /Ura ratio might assist in monitoring the alteration of DPD activity levels in capecitabine treatments.

Pharmacokinetic analysis of metronomic capecitabine in refractory metastatic colorectal cancer patients.

The aim of the present study was to assess the pharmacokinetics (PK) of metronomic capecitabine and its metabolites in a population of refractory metastatic colorectal cancer (mCRC) patients. Thirty-four patients (M/F, 22/12) with a diagnosis of mCRC received capecitabine 800 mg p.o. twice a day and cyclophosphamide 50 mg/day p.o. Blood samples were collected at baseline, 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h and 5 h at day 1 after capecitabine administration. Plasma concentrations of capecitabine and its metabolites were measured by high performance liquid chromatography and the main PK parameters were calculated. Maximum plasma concentrations (Cmax) of capecitabine (11.51 ± 9.73 µg/ml) occurred at 0.5 h, whereas the Cmax of 5'-deoxy-5-fluorocytidine (5'-DFCR; 2.45 ± 2.93 µg/ml), 5'-deoxy-5-fluorouridine (5'-DFUR; 6.43 ± 8.2 µg/ml), and 5-fluorouracil (5-FU; 0.24 ± 0.16 µg/ml) were found at 1 h, 1.5 h and 1 h, respectively. Capecitabine, 5'-DFCR, 5'-DFUR and 5-FU AUCs at day 1 were 21.30 ± 10.78, 5.2 ± 4.6, 19.59 ± 3.83 and 0.66 ± 0.77 hxµg/ml, respectively. In conclusion, low doses of capecitabine were rapidly absorbed and extensively metabolized, achieving measurable plasma concentrations in a heavily pretreated population of patients.

Capecitabine bioequivalence in healthy volunteers.

Capecitabine is a prodrug and is selectively activated by tumor cells to its cytotoxic moiety, 5-fluorouracil, by thymidine phosphorylase, which is generally expressed at high levels in tumors. Clinical and pharmacokinetic studies of capecitabine have been performed in patients with cancer. This study aims to evaluate the bioequivalence of two capecitabine formulations (150-mg tablet) using healthy male subjects under nonfasting conditions. The study was conducted as an open, randomized, three-period, semi-replicated design with three sequences (RRT, RTR, TRR) with a 1-week washout interval. The subjects were selected for the study after having their health status previously assessed by a clinical evaluation and laboratory tests (biochemical and hematological parameters, and urinalysis). A single capecitabine tablet (150 mg) was given in each occasion. Plasma capecitabine concentrations were analyzed by liquid chromatography coupled with tandem mass spectrometry (HPLC/MS/MS) with positive ion electrospray ionization using multiple reactions monitoring (MRM). The geometric mean and 90% confidence intervals (CI) of capecitabine/Xeloda® (T/R) percent ratio were 104.34% (98.74 - 110.25%) for AUClast, 103.06% (97.48 - 108.96%) for AUCinf, and 104.07% (88.13 - 122.90%) for Cmax. Since the 90% CI for Cmax, AUClast, and AUCinf ratios were all inside the 80 - 125% interval proposed by the US Food and Drug Administration Agency, it was concluded that the capecitabine formulation elaborated by Eurofarma Laboratórios Ltda. is bioequivalent to Xeloda® formulation for both the rate and the extent of absorption. The drug was well tolerated by the subjects, indicating that it is safe to perform capecitabine bioequivalence studies in healthy male subjects.
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A rapid and simple HPTLC assay for therapeutic drug monitoring of capecitabine in colorectal cancer patients.

Capecitabine is a prodrug of 5-flurouracil, employed as a broad spectrum chemotherapeutic agent. It is also used as monotherapy or a combination chemotherapy agent for the treatment of colorectal cancer. Capecitabine is administered in combination with oxaliplatin and hence it is essential to determine that co-administration does not affect its metabolism. To determine the plasma concentration of capecitabine a simple HPTLC method was developed and validated. Blood samples from 12 patients with colorectal cancer were collected and analyzed by the HPTLC method with a reference internal standard. Out of these 12 patients, six were treated with capecitabine monotherapy and another six were treated with capecitabine + oxaliplatin combination therapy. The results of analysis indicated that there was no significant drug-drug interaction and the co-administration of oxaliplatin did not affect the metabolism of capecitabine. This method is sensitive, robust and specific and allows analysis of multiple samples simultaneously, making it suitable for therapeutic drug monitoring of capecitabine.

Capecitabine lipid nanoparticles for anti-colon cancer activity in 1,2-dimethylhydrazine-induced colon cancer: preparation, cytotoxic, pharmacokinetic, and pathological evaluation.

The cornerstone of this investigation is to determine the pharmacokinetic and histopathological behavior of solid lipid nanoparticles of capecitabine (CB-SLNs) in 1,2-dimethylhydrazine (DMH) induced colon cancer. The nanoparticles were prepared by microemulsion method. CB-SLNs were characterized for an optimal system. The cytotoxicity of CB-SLNs was evaluated by using MTT assay method. Further, pharmacokinetic and histopathological behavior of SLNs were studied in DMH induced colon cancer rats. The optimized nanoparticles have the particle size, zeta potential, and entrapment efficiency of 145.6 ± 3.6 nm, -26.9 ± 2.7 mV, and 88.33 ± 3.74%, respectively. Particles of CB were nearly spherical in shape and converted to amorphous form revealed by SEM and DSC, XRD studies. The nanoparticles showed dose-dependent cytotoxicity activity from 10 to 125 µg/mL compared with suspension. Pharmacokinetic studies revealed that 2.7-folds enhancement in the oral bioavailability and in aberrant crypt foci number, apoptotic index comparison with suspension formulation.

Multiple response optimisation of processing and formulation parameters of pH sensitive sustained release pellets of capecitabine for targeting colon.

PURPOSE: To optimise the Eudragit/Surelease®-coated pH-sensitive pellets for controlled and target drug delivery to the colon tissue and to avoid frequent high dosing and associated side effects which restrict its use in the colorectal-cancer therapy. METHODS: The pellets were prepared using extrusion-spheronisation technique. Box-Behnken and 32 full factorial designs were applied to optimise the process parameters [extruder sieve size, spheroniser-speed, and spheroniser-time] and the coating levels [%w/v of Eudragit S100/Eudragit-L100 and Surelease®], respectively, to achieve the smooth optimised size pellets with sustained drug delivery without prior drug release in upper gastrointestinal tract (GIT). RESULTS: The design proposed the optimised batch by selecting independent variables at; extruder sieve size (X1 = 1 mm), spheroniser speed (X2 = 900 revolutions per minute, rpm), and spheroniser time (X3 = 15 min) to achieve pellet size of 0.96 mm, aspect ratio of 0.98, and roundness 97.42%. The 16%w/v coating strength of Surelease® and 13%w/v coating strength of Eudragit showed pH-dependent sustained release up to 22.35 h (t99%). The organ distribution study showed the absence of the drug in the upper part of GIT tissue and the presence of high level of capecitabine in the caecum and colon tissue. Thus, the presence of Eudragit coat prevent the release of drug in stomach and the inner Surelease® coat showed sustained drug release in the colon tissue. CONCLUSION: The study demonstrates the potential of optimised Eudragit/Surelease®-coated capecitabine-pellets for effective colon-targeted delivery system to avoid frequent high dosing and associated systemic side effects of drug.

Pharmacokinetic model analysis of interaction between phenytoin and capecitabine.

OBJECTIVE: Recent reports have shbown an increase in serum phenytoin levels resulting in phenytoin toxicity after initiation of luoropyrimidine chemotherapy. To prevent phenytoin intoxication, phenytoin dosage must be adjusted. We sought to develop a pharmacokinetic model of the interaction between phenytoin and capecitabine. METHODS: We developed the phenytoin-capecitabine interaction model on the assumption that fluorouracil (5-FU) inhibits cytochrome P450 (CYP) 2C9 synthesis in a concentration- dependent manner. The plasma 5-FU concentration after oral administration of capecitabine was estimated using a conventional compartment model. Nonlinear pharmacokinetics of phenytoin was modeled by incorporating the Michaelis-Menten equation to represent the saturation of phenytoin metabolism. The resulting model was fitted to data from our previously-reported cases. RESULTS: The developed phenytoincapecitabine interaction model successfully described the profiles of serum phenytoin concentration in patients who received phenytoin and capecitabine concomitantly. The 50% inhibitory 5-FU concentration for CYP2C9 synthesis and the degradation rate constant of CYP2C9 were estimated to be 0.00310 ng/mL and 0.0768 day-1, respectively. This model and these parameters allow us to predict the appropriate phenytoin dosage schedule when capecitabine is administered concomitantly. CONCLUSIONS: This newly-developed model accurately describes changes in phenytoin concentration during concomitant capecitabine chemotherapy, and it may be clinically useful for predicting appropriate phenytoin dosage adjustments for maintaining serum phenytoin levels within the therapeutic range.

Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data.

BACKGROUND: The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD (DPYD), including DPYD*2A and c.2846A>T. Three other variants-DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A-have been associated with DPD deficiency, but no definitive evidence for the clinical validity of these variants is available. The primary objective of this systematic review and meta-analysis was to assess the clinical validity of c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity. METHODS: We did a systematic review of the literature published before Dec 17, 2014, to identify cohort studies investigating associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and severe (grade ≥3) fluoropyrimidine-associated toxicity in patients treated with fluoropyrimidines (fluorouracil, capecitabine, or tegafur-uracil as single agents, in combination with other anticancer drugs, or with radiotherapy). Individual patient data were retrieved and analysed in a multivariable analysis to obtain an adjusted relative risk (RR). Effect estimates were pooled by use of a random-effects meta-analysis. The threshold for significance was set at a p value of less than 0·0167 (Bonferroni correction). FINDINGS: 7365 patients from eight studies were included in the meta-analysis. DPYD c.1679T>G was significantly associated with fluoropyrimidine-associated toxicity (adjusted RR 4·40, 95% CI 2·08-9·30, p<0·0001), as was c.1236G>A/HapB3 (1·59, 1·29-1·97, p<0·0001). The association between c.1601G>A and fluoropyrimidine-associated toxicity was not significant (adjusted RR 1·52, 95% CI 0·86-2·70, p=0·15). Analysis of individual types of toxicity showed consistent associations of c.1679T>G and c.1236G>A/HapB3 with gastrointestinal toxicity (adjusted RR 5·72, 95% CI 1·40-23·33, p=0·015; and 2·04, 1·49-2·78, p<0·0001, respectively) and haematological toxicity (adjusted RR 9·76, 95% CI 3·03-31·48, p=0·00014; and 2·07, 1·17-3·68, p=0·013, respectively), but not with hand-foot syndrome. DPYD*2A and c.2846A>T were also significantly associated with severe fluoropyrimidine-associated toxicity (adjusted RR 2·85, 95% CI 1·75-4·62, p<0·0001; and 3·02, 2·22-4·10, p<0·0001, respectively). INTERPRETATION: DPYD variants c.1679T>G and c.1236G>A/HapB3 are clinically relevant predictors of fluoropyrimidine-associated toxicity. Upfront screening for these variants, in addition to the established variants DPYD*2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines. FUNDING: None.

Pharmacokinetics and Comparative Bioavailability of Test or Reference Capecitabine and Discrepant Pharmacokinetics Among Various Tumors in Chinese Solid Cancer Patients.

The main objective of this study was to compare the pharmacokinetic (PK) bioequivalence of two capecitabine tablets and explore the different PK profiles of various tumors in Chinese patients with cancer. All 76 patients with a confirmed cancer diagnosis were included in this study. A single dose of 2000 mg of test or reference capecitabine (Xeloda, Hoffmann-La Roche) was orally administered postprandially. After 24 hours of washout, the patients were administered the test or the reference capecitabine alternately. PK samples were taken at the time of predose up to 6 hours postdose. Bioequivalence evaluation was performed using the geometric mean ratios of peak concentration in plasma (Cmax) , area under the concentration-time curve from time 0 to 6 h (AUC0-t) , and area under the concentration-time curve from time 0 to infinity (AUC0-∞ ) for capecitabine and 5-fluorouracil (5-FU). In this study, 90% confidence intervals of test/reference mean ratios of Cmax , AUC0-t , AUC0-∞ of capecitabine and 5-FU were in the range of 80%-125%. Both the test and reference capecitabine regimens were well tolerated in this study. Furthermore, we found that patients with esophageal-gastrointestinal cancers had higher exposure to capecitabine and a shorter time to Cmax (Tmax) than those with breast cancer. In conclusion, a single oral dose of 2000 mg of test capecitabine tablets after postprandial administration was bioequivalent to the reference drug.

Diurnal Changes in Capecitabine Clock-Controlled Metabolism Enzymes Are Responsible for Its Pharmacokinetics in Male Mice.

The circadian timing system controls absorption, distribution, metabolism, and elimination processes of drug pharmacokinetics over a 24-h period. Exposure of target tissues to the active form of the drug and cytotoxicity display variations depending on the chronopharmacokinetics. For anticancer drugs with narrow therapeutic ranges and dose-limiting side effects, it is particularly important to know the temporal changes in pharmacokinetics. A previous study indicated that pharmacokinetic profile of capecitabine was different depending on dosing time in rat. However, it is not known how such difference is attributed with respect to diurnal rhythm. Therefore, in this study, we evaluated capecitabine-metabolizing enzymes in a diurnal rhythm-dependent manner. To this end, C57BL/6J male mice were orally treated with 500 mg/kg capecitabine at ZT1, ZT7, ZT13, or ZT19. We then determined pharmacokinetics of capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine (5'DFCR), 5'-deoxy-5-fluorouridine (5'DFUR), 5-fluorouracil (5-FU), in plasma and liver. Results revealed that plasma Cmax and AUC0-6h (area under the plasma concentration-time curve from 0 to 6 h) values of capecitabine, 5'DFUR, and 5-FU were higher during the rest phase (ZT1 and ZT7) than the activity phase (ZT13 and ZT19) (p < 0.05). Similarly, Cmax and AUC0-6h values of 5'DFUR and 5-FU in liver were higher during the rest phase than activity phase (p < 0.05), while there was no significant difference in liver concentrations of capecitabine and 5'DFCR. We determined the level of the enzymes responsible for the conversion of capecitabine and its metabolites at each ZT. Results indicated the levels of carboxylesterase 1 and 2, cytidine deaminase, uridine phosphorylase 2, and dihydropyrimidine dehydrogenase (p < 0.05) are being rhythmically regulated and, in turn, attributed different pharmacokinetics profiles of capecitabine and its metabolism. This study highlights the importance of capecitabine administration time to increase the efficacy with minimum adverse effects.

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.

Effect of the Proton Pump Inhibitor Esomeprazole on the Systemic Exposure of Capecitabine: Results of A Randomized Crossover Trial.

Retrospective data suggest that gastric acid reduction by proton pump inhibitors (PPIs) impairs the dissolution and subsequent absorption of capecitabine, and thus potentially reduces the capecitabine exposure. Therefore, we examined prospectively the effect of esomeprazole on the pharmacokinetics of capecitabine. In this randomized crossover study, patients with cancer were assigned to 2 sequence groups, each consisting of 3 phases: capecitabine with esomeprazole administration 3 hours before (phase A), capecitabine alone (phase B), and capecitabine concomitant with cola and esomeprazole co-administration 3 hours before (phase C). The primary end point was the relative difference (RD) in exposure to capecitabine assessed by the area under the plasma concentration-time curve from zero to infinity (AUC0-inf ) and analyzed by a linear mixed effect model. Twenty-two evaluable patients were included in the analysis. After esomeprazole, there was a 18.9% increase in AUC0-inf of capecitabine (95% confidence interval (CI) -10.0% to 57.0%, P = 0.36). In addition, capecitabine half-life was significantly longer after esomeprazole (median 0.63 hours vs. 0.46 hours, P = 0.005). Concomitant cola did not completely reverse the effects observed after esomeprazole (RD 3.3% (95% CI -16.3 to 27.4%, P = 1.00). Capecitabine exposure is not negatively influenced by esomeprazole cotreatment. Therefore, altered capecitabine pharmacokinetics do not explain the assumed worse clinical outcome of PPI-cotreated patients with cancer.

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.

Population pharmacokinetic and pharmacodynamic modeling of capecitabine and its metabolites in breast cancer patients.

PURPOSE: The present study was performed to examine relationships between systemic exposure of capecitabine metabolites (5-FU, 5'-DFCR and 5'-DFUR) and toxicity or clinical response in patients with metastatic breast cancer. METHODS: A population pharmacokinetic model for capecitabine and its three metabolites was built. Typical parameter values, characteristics of random distributions, associated with parameters, and covariates impact were estimated. Area under the curve (AUC) were computed for 5-FU and compared with grades of toxicity. Pharmacokinetic modeling was based on data collected on the first treatment cycle. Toxicity was assessed on the two first treatment cycles. RESULTS: The study was conducted in 43 patients. The population pharmacokinetic model (a one-compartment model per compound) was able to capture the very complex absorption process of capecitabine. Statistically significant covariates were cytidine deaminase, alkaline phosphatase and dihydrouracilemia (UH2)/uracilemia (U) ratio. UH2/U ratio was the most significant covariate on 5-FU elimination and CDA on the transformation of 5'-DFCR in 5'-DFUR. A trend was observed between 5-FU AUC and thrombopenia toxicity grades, but not with other toxicities. Best clinical response was not linked to systemic exposure of capecitabine metabolites. CONCLUSION: In our study, we propose a model able to describe, meanwhile, and its main metabolites, with a complex absorption process and inclusion of enzyme activity covariates such as CDA and UH2/U ratio. Trial registration Eudract 2008-004136-20, 2008/11/26.

Development of biodegradable thin films for efficient, specific and controlled delivery of capecitabine.

Cancer is the leading cause of death worldwide. Capecitabine (CP) shows severe side effects because of early metabolism in stomach that affects the normal cells and organs, particularly liver and stomach. In this scope, we report the biocompatible, nontoxic polymeric thin films loaded with anti-cancer drug, CP for target specific, sublingual delivery of CP. Chitosan (CS) and polyvinyl alcohol (PVA) were used as biodegradable polymers alongwith glutaraldehyde (GLA) cross linker. CP-loaded thin films (TFCP1-TFCP5) were fabricated by solvent casting method. The results of Fourier transform infrared spectroscopy confirmed the presence of CP and polymers (CS and PVA) with GLA which binds through hydrogen bonding, and compatibility of drug with different excipients. Thermogravemetric analysis showed that the thin films are highly stable while differential scanning calorimeter thermograms confirmed the complete miscibility/entrapment of CP within PVA/CS thin film matrix. X-ray diffraction patterns revealed the molecular ineractions between CP and polymer matrix. High degree of swelling index of thin films at pH 7.4 was observed in comparison to pH 5.5. CP release studies in acetate (pH 5.5) and phosphate buffer (pH 7.4) showed that the thin films swell and result in drug diffusion faster in phosphate buffer through diffusion governed by Higuchi's model. Cytotoxicity results displayed that CPTFs killed MCF-7 and T47D (human breast adenocarcinoma) cells more effectively as compared to CP alone. The results of adhesion assay also showed that the PVA and CS both are safe and biocompatible. TFCP1 and TFCP3 thin films efficiently induced the apoptosis as compared to CP alone. The improved ability of TFCP1 and TFCP3 to induce cytotoxicity in MCF-7 cells reflects the potential of these thin films for targeted drug delivery. The CPTFs were stable for 4 months at 4 °C/60% ± 2%RH and 25 °C/70% ± 2%RH. In conclusion, the thin film formulations showed target specific controlled and burst release properties and thus could prove to be effective for human breast cancer treatment.

Population Pharmacokinetics of Intracellular 5-Fluorouridine 5'-Triphosphate and its Relationship with Hand-and-Foot Syndrome in Patients Treated with Capecitabine.

Capecitabine is an oral pro-drug of 5-fluorouracil. Patients with solid tumours who are treated with capecitabine may develop hand-and-foot syndrome (HFS) as side effect. This might be a result of accumulation of intracellular metabolites. We characterised the pharmacokinetics (PK) of 5-fluorouridine 5'-triphosphate (FUTP) in peripheral blood mononuclear cells (PBMCs) and assessed the relationship between exposure to capecitabine or its metabolites and the development of HFS. Plasma and intracellular capecitabine PK data and ordered categorical HFS data was available. A previously developed model describing the PK of capecitabine and metabolites was extended to describe the intracellular FUTP concentrations. Subsequently, a continuous-time Markov model was developed to describe the development of HFS during treatment with capecitabine. The influences of capecitabine and metabolite concentrations on the development of HFS were evaluated. The PK of intracellular FUTP was described by an one-compartment model with first-order elimination (ke,FUTP was 0.028 h-1 (95% confidence interval 0.022-0.039)) where the FUTP influx rate was proportional to the 5-FU plasma concentrations. The predicted individual intracellular FUTP concentration was identified as a significant predictor for the development and severity of HFS. Simulations demonstrated a clear exposure-response relationship. The intracellular FUTP concentrations were successfully described and a significant relationship between these intracellular concentrations and the development and severity of HFS was identified. This model can be used to simulate future dosing regimens and thereby optimise treatment with capecitabine.

Impact of pretreatment dihydropyrimidine dehydrogenase genotype-guided fluoropyrimidine dosing on chemotherapy associated adverse events.

Consensus guidelines exist for genotype-guided fluoropyrimidine dosing based on variation in the gene dihydropyrimidine dehydrogenase (DPYD). However, these guidelines have not been widely implemented in North America and most studies of pretreatment DPYD screening have been conducted in Europe. Given regional differences in treatment practices and rates of adverse events (AEs), we investigated the impact of pretreatment DPYD genotyping on AEs in a Canadian context. Patients referred for DPYD genotyping prior to fluoropyrimidine treatment were enrolled from December 2013 through November 2019 and followed until completion of fluoropyrimidine treatment. Patients were genotyped for DPYD c.1905+1G>A, c.2846A>T, c.1679T>G, and c.1236G>A. Genotype-guided dosing recommendations were informed by Clinical Pharmacogenetics Implementation Consortium guidelines. The primary outcome was the proportion of patients who experienced a severe fluoropyrimidine-related AE (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Secondary outcomes included early severe AEs, severe AEs by toxicity category, discontinuation of fluoropyrimidine treatment due to AEs, and fluoropyrimidine-related death. Among 1394 patients, mean (SD) age was 64 (12) years, 764 (54.8%) were men, and 47 (3.4%) were DPYD variant carriers treated with dose reduction. Eleven variant carriers (23%) and 418 (31.0%) noncarriers experienced a severe fluoropyrimidine-related AE (p = 0.265). Six carriers (15%) and 284 noncarriers (21.1%) experienced early severe fluoropyrimidine-related AEs (p = 0.167). DPYD variant carriers treated with genotype-guided dosing did not experience an increased risk for severe AEs. Our data support a role for DPYD genotyping in the use of fluoropyrimidines in North America.

Worse capecitabine treatment outcome in patients with a low skeletal muscle mass is not explained by altered pharmacokinetics.

BACKGROUND: A low skeletal muscle mass (SMM) has been associated with increased toxicity and shorter survival in cancer patients treated with capecitabine, an oral prodrug of 5-fluorouracil (5-FU). Capecitabine and its metabolites are highly water-soluble and, therefore, more likely to distribute to lean tissues. The pharmacokinetics (PK) in patients with a low SMM could be changed, for example, by reaching higher maximum plasma concentrations. In this study, we aimed to examine whether the association between a low SMM and increased toxicity and shorter survival could be explained by altered PK of capecitabine and its metabolites. METHODS: Previously, a population PK model of capecitabine and metabolites in patients with solid tumors was developed. In our analysis, we included patients from this previous analysis for which evaluable abdominal computed tomography (CT)-scans were available. SMM was measured on CT-scans, by single slice evaluation at the third lumbar vertebra, using the Slice-o-Matic software. The previously developed population PK model was extended with SMM as a covariate, to assess the association between SMM and capecitabine and metabolite PK. RESULTS: PK and SMM data were available from 151 cancer patients with solid tumors. From the included patients, 55% had a low SMM. No relevant relationships were found between SMM and the PK parameters of capecitabine and, the active and toxic metabolite, 5-FU. SMM only correlated with the PK of the, most hydrophilic, but inactive and non-toxic, metabolite α-fluoro-ß-alanine (FBAL). Patients with a low SMM had a smaller apparent volume of distribution and lower apparent clearance of FBAL. CONCLUSIONS: No alterations in PK of capecitabine and the active and toxic metabolite 5-FU were observed in patients with a low SMM. Therefore, the previously identified increased toxicity and shorter survival in patients with a low SMM, could not be explained by changes in pharmacokinetic characteristics of capecitabine and metabolites.