Individual 5FU-dose adaptation schedule using bimonthly pharmacokinetically modulated LV5FU2 regimen: a feasibility study in patients with advanced colorectal cancer.

AIM OF THE STUDY: SFU-dose adaptation optimal schedule using bimonthly LV5FU2 regimen was modulated by previously validated individual pharmacokinetic parameters, in 38 patients with advanced colorectal cancer. METHODS: At the 1st cure, 5F-U pharmacokinetic parameters (particularly the area under curve (AUC) in mg.h/l.m2) were calculated in all patients. In 19 patients (A), 5FU infusion doses were progressively increased from 25 to 50% (at every cycle), according to AUC levels from 2nd to 6th; in 19 consecutive patients (B), 5FU infusion doses were increased, at the same time, at the 2nd cure, according to a protocol taking in account AUC at the 1st cure: increase of 150% it AUC < 5, of 100% if 5 < AUC < 10, of 50% if 10 < AUC < 15, of 25% if 15 < AUC < 20 in case of toxicity < grade 3. RESULTS: a) AUC in all patients, at the beginning of the treatment averaged 9.05 +/- 3.115 (range from 3.9 to 16.41). Large interindividual variability was observed. b) FU infusion doses at the 2nd cure, increased 40% in group A and 82% in group B. Corresponding AUC increased respectively of 42% and 96%. 3-WHO toxicity 23 (per cycle) occurred not very frequently (8% haematological, 6% digestive and 2% cutaneous toxicity) and remained acceptable. CONCLUSION: This feasibility study established a 5FU-dose intensification optimal strategy within the bimonthly LV5FU2 schedule with a control for the risk of toxicity. This study constitutes the basis for a multicentre phase II trial to evaluate the importance of this approach in terms of efficacy and survival.

Plasma and salivary pharmacokinetics of 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer receiving 5-FU bolus plus continuous infusion with high-dose folinic acid.

The comparative saliva/plasma pharmacokinetics of 5-fluorouracil (5-FU) were investigated in 21 patients with metastatic colorectal cancer receiving high-dose folinic acid (LV (leucovorin) 200 mg/m2) followed by 5-FU bolus (400 mg/m2) and continuous infusion (600, 750, 900 or 1200 mg/m2) on days 1 and 2. Quantitation of unchanged drug was assessed by a highly specific high-performance liquid chromatographic method. Large patient-to-patient variations in plasma and saliva 5-FU concentrations were observed. Saliva pharmacokinetics could be described using a bi-exponential pattern. The half-life of the rapid phase averaged 8.0 min, and was of the same order of magnitude as the 5-FU elimination half-life determined from plasma data. The half-life of the terminal part of the curve averaged 8 h; such decrease in salivary concentrations could be due to changes in salivary gland function caused by 5-FU, which results in reduced salivary flow rate. Between individual 5-FU concentrations in parotid saliva and plasma a statistically significant straight line could be fitted with a coefficient of correlation of 0.675. Moreover, the risk of developing 5-FU-related mucositis was significantly linked to 5-FU salivary exposure. Diarrhoea was the most frequent toxicity encountered during the trial.

Circadian rhythm of 5-fluorouracil population pharmacokinetics in patients with metastatic colorectal cancer.

PURPOSE: The purpose of this work was to estimate the population pharmacokinetic parameters of 5-fluorouracil (5-FU) in patients with advanced colorectal cancer using circadian change kinetics. METHODS: Eighty-five patients (32 females, 53 males) were enrolled onto this study. All patients received folinic acid (200 mg/m(2)) by intravenous infusion over 2 h followed by a 5-FU loading dose (400 mg/m(2)) and then continuous infusion (600 mg/m(2)) for 22 h. This whole regimen was repeated on day 2 and was given on a 14-day cycle. Plasma 5-FU determinations were performed by high-performance liquid chromatography with ultraviolet absorbance detection. Pharmacokinetic analyses were performed using the NONMEM computer program through the Visual-NM graphical interface. An open one-compartment pharmacokinetic model with zero-order input rate was used to describe the kinetics of 5-FU; moreover, circadian time-dependent changes in 5-FU concentrations were taken into account in the model. The circadian model was defined as the sum of two cyclic components; the amplitude of the first cyclic component (over 24 h) was about 30% of the average clearance and the amplitude of the second cyclic component (over 12 h) was about 50% of the amplitude of the first component. The acrophase (peak) times of the first and the second periodic component were 04 h 12 m and 00 h 25 m, respectively. The potential sources of variability on the population parameters (65 patients) were investigated using patient's sex, body area, age, body weight, height, liver enzymes and serum creatinine as covariables. RESULTS: Only the estimated clearance circadian changes were different for the two sexes. The population parameter estimates of mean clearance (CL(mean)) and initial volume of distribution (V), were as follows: the male subgroup showed a CL(mean) value twice larger (125 l/h) than the value observed in the female subgroup (65 l/h), and V = 21 l. A validation group of 20 additional patients was used to evaluate the predictive performances of the population parameters. The individual pharmacokinetic parameters were computed by means of a Bayesian fitting procedure. From the resulting individualized parameter values, concentrations of 5-FU in the plasma were calculated. To evaluate the performance of the Bayesian estimation, the experimental concentrations were compared with the predicted ones. CONCLUSION: In conclusion, a chronomodulated delivery schedule of 5-FU should be performed, using a perfusion rate inversely proportional to the circadian variations of clearance in order to maintain stable 5-FU plasma levels. Such a treatment schedule may result in increased effectiveness of the treatment and decreased occurrence of drug-associated side-effects. The present study develops a complete procedure to efficiently estimate 5-FU clearance in order to optimize dosage regimens in individual patients.

Methyl-beta-cyclodextrin and doxorubicin pharmacokinetics and tissue concentrations following bolus injection of these drugs alone or together in the rabbit.

The purpose of this work was to determine the pharmacokinetics and the tissue concentrations of methyl-beta-cyclodextrin (MEBCD) and doxorubicin (DOX) in rabbits following administration of MEBCD and DOX, alone or in combination. MEBCD (200 mg/kg) and DOX (1 mg/kg) were intravenously injected to white New Zealand rabbits and blood samples were obtained over a 48-h period after administration. After this period, administration was repeated and animals were killed 1, 2 or 4 h after injection. Heart, liver and kidney were then removed. MEBCD and DOX analysis in plasma and tissues was performed using two HPLC methods with fluorimetric detection. MEBCD pharmacokinetic profile was consistent with a two-compartment model (t1/2 alpha: 30 min; t1/2 beta: 7 h). Co-administration with DOX did not modify the main pharmacokinetic parameters of MEBCD. However, C5 min, t1/2 alpha, t1/2 beta and AUCinfinity were decreased by the co-administration of DOX with MEBCD compared to DOX alone. Assays of excised tissues showed that DOX enhanced the cardiac, renal and hepatic concentrations of MEBCD. On the other hand, MEBCD did not alter the cardiac distribution of DOX, while renal and hepatic distribution profiles were modified. In this study, the pharmacokinetic parameters of MEBCD injected intravenously were determined for the first time. DOX did not enhance MEBCD pharmacokinetic profile but MEBCD reduced the distribution half-life of DOX. Tissue determination showed that MEBCD did not enhanced the cardiac accumulation of DOX, which is auspicious for further in vivo experiments using the co-administration of DOX and MEBCD.

Pharmacokinetics of 5-fluorouracil (5-FUra) in patients with metastatic colorectal cancer receiving 5-FUra bolus plus continuous infusion with high dose folinic acid (LV5FU2).

The pharmacokinetics of 5-fluorouracil (5-FUra) were investigated in 16 patients with metastatic colorectal cancer receiving high-dose folinic acid (LV 200 mg/m2) followed by 5-FUra bolus (400 mg/m2) and continuous infusion (600 mg/m2) on days 1 and 2. Quantitation of unchanged drug was assessed by a highly specific high-performance liquid chromatographic method. The concentrations of 5-FUra at the end of the loading dose averaged 30.7 +/- 13.2 micrograms/ml (i.e., 236 microM). The steady-state plasma concentration averaged 0.31 +/- 0.11 microgram/ml (i.e., 2.4 microM). 5-FUra plasma levels declined rapidly after the end of infusion with an apparent elimination half-life of 7.08 +/- 3.21 minutes. Clearance ranged from 776 to 3023 ml/min/m2. Large patient-to-patient variations in plasma 5-FUra concentrations were observed. No toxicity greater than WHO grade 2 was seen. One patient experienced grade 1 stomatitis and two others experienced grade 1 and 2 myelosuppression. One patient developed diarrhoea and another suffered asthenia. Nausea and vomiting were observed in 5 patients.

High-performance liquid chromatographic assay for methyl-beta-cyclodextrin in plasma and cell lysate.

This paper describes a high-performance liquid chromatographic method with fluorescence detection for the analysis of methyl-beta-cyclodextrin (MEBCD) in plasma and cell lysate, after in situ complexation with 1-naphthol. The size-exclusion HPLC column packed with TSK 3000 SW gel, was equilibrated with an eluent mixture composed of methanol and purified water (2:98, v/v) containing 10(-4) M 1-naphthol as a fluorophore. The detection is based on fluorescence enhancement caused by the formation of inclusion complexes and was performed at 290 and 360 nm for excitation and emission, respectively. The method involved a simple treatment of the samples with chloroform. Daunorubicin was used as internal standard. Limits of quantitation were 0.8 microM in plasma and 0.5 microM in cell lysate. Detection limits of 0.5 microM (50 pmol) and 0.3 microM (30 pmol) were obtained for MEBCD in the two media, respectively. Linear detection response was obtained for concentrations ranging from 1 to 100 microM in plasma and cell lysate. Recovery from plasma proved to be more than 40%. Precision, expressed as C.V. was in the range of 4 to 11%. Accuracy ranged from 89 to 105%.

Determination of 5-fluorouracil and its main metabolites in plasma by high-performance liquid chromatography: application to a pharmacokinetic study.

This paper describes a relatively simple and sensitive high-performance liquid chromatographic assay (HPLC) with ultraviolet absorbance detection for 5-fluorouracil (5-FUra) and its two main metabolites, 5-fluorouridine (5-FUrd) and 5-fluoro-2'-deoxyuridine (5-FdUrd), in plasma. In this study, two plasma clean-up procedures involving addition of internal standard, solid-phase and liquid-liquid extractions have been developed. A reversed-phase Kromasil C18 column was used. The detection was performed at 268 nm for 5-FUra and at 275 nm for the two metabolites. Linear detection responses were obtained for concentrations ranging from 25 to 1000 ng/ml. The average recovery from plasma was 35, 42 and 48% for 5-FUra, 5-FUrd and 5-FdUrd, respectively. Precision, expressed as C.V., ranged from 2.7 to 13% and the mean recovery from 94 to 105%. The limits of quantitation and detection of the three analytes were 20 and 10 ng/ml, respectively. The method was used to monitor the pharmacokinetic profile of 5-FUra and its two metabolites in patients with metastatic colorectal cancer.

High-performance liquid chromatographic assay for melphalan in human plasma. Application to pharmacokinetic studies.

This paper describes a simple, rapid and reproducible high-performance liquid chromatographic method (HPLC) with ultraviolet absorbance detection for the analysis of melphalan in plasma. The HPLC column was an Ultrasphere ODS (5 microns) and the eluent was composed of methanol, purified water and acetic acid (49.5:49.5:1, v/v). The detection was performed at 261 nm. The method involved a simple treatment of the samples with methanol. The propylparaben was used as internal standard. Linear detection response was obtained for concentrations ranging from 50 to 2500 ng/ml. Recovery from plasma proved to be more than 90%. Precision, expressed as C.V., was in the 0.5 to 9% range. Accuracy ranged from 95 to 102%. This method was used to determine the pharmacokinetic parameters of melphalan following high-dose (140 mg/m2) intravenous administration in patients with advanced malignancies undergoing peripheral blood hematopoietic progenitor-cell transplantation.