[Securing the patient's care path receiving oral anticancer therapy: Experimentation around a pharmaceutical hospital-to-community liaison]. / Sécurisation du parcours de soins du patient sous thérapie orale en oncologie : expérimentation autour d'un lien pharmaceutique hôpital­ville.

Due to the increasing prescription of oral anticancer therapies, the inpatient care pathway has shifted to an outpatient care pathway. This transformation requires an interdisciplinary coordination to provide a continuum of care and ensure therapeutic monitoring, as well as patient safety. To better support patients on oral anticancer therapies, a task group named "hospital-to-community pharmacist coordination" has been set up to create tools aiming at standardising the information exchanged between ambulatory and hospital pharmacists. A retrospective study examined the utilisation of the tools over a period of one year. The task group identified the expectations of all parties regarding the care pathways of patients undergoing oral chemotherapy, which lead to the creation of computerised exchange tools (integrated into the computerised patient's medical file). Over the course of this study, the cancer centre's pharmaceutical team contacted 425 ambulatory pharmacists regarding the prescription of oral chemotherapy to patients. Forty-two follow-ups from ambulatory pharmacists, gathering information on 34 patients, were submitted to the cancer centre pharmacists (7,7%). These first follow-ups allowed pharmaceutical responses regarding patient compliance, drug interaction and toxicities.

[Study impacto: Descriptive analyzis of pharmacist's clinical practice in onco-hematology]. / Étude impacto : analyse descriptive des pratiques de pharmacie clinique en cancérologie.

Pharmaceutical analyses of chemotherapy prescriptions by hospital pharmacists are activities codified by regulation and rules (bon usage). The involvement of the pharmacists in clinical pharmacy activities in the oncology setting is not clearly identified, justifying the development of a mapping of these activities from a questionnaire addressed to the professionals. One hundred and seven centers have participated to this study at the national level (overall participation rate of 32.4%). More than 95% of them used a computerized ordering system and three quarter of them submit the introduction of new compounds to an analysis by the drug therapeutic committee. Prescription analysis allowed detecting around 2% of errors from the current prescription. Clinical pharmacist participates to tumor boards of onco-hematology (RCP) at a level of 46% for senior pharmacist and 42% for junior pharmacist. This involvement in the RCP allowed anticipating protocol's modification and temporary used authorization. Ninety-two percent of the senior pharmacists estimate that they highlight the risk of no reimbursement for prescription out of the guideline during RCP, resulting to a modification of the prescription for 40% of them. This level of intervention is lower with respectively 64% and 10% for the juniors. This study underlines the expert value of the clinical pharmacist dedicated to oncology setting in pre and post analysis prescriptions. It could be targeted by a prospective analysis of both clinical and pharmacoeconomics impact of these interventions.

SFPO and ESOP recommendations for the practical stability of anticancer drugs: an update.

The recommendations for the practical stability of anticancer drugs published in 2010 by the French Society of Hospital Pharmacists (SFPO) and the European Society of Oncology Pharmacists (ESOP) have been updated. Ten new molecules have been included (asparaginase, azacitidine, bevacizumab, clofarabine, eribuline mesylate, folinate sodium, levofolinate calcium, nelarabine, rituximab, temsirolimus).

Stability of ready-to-use temsirolimus infusion solution (100mg/L) in polypropylene containers under different storage conditions.

The aim of this study was to determine the stability of ready-to-use temsirolimus infusion solutions under different storage conditions. Solutions were prepared in polypropylene containers by adding temsirolimus injection to 0.9% sodium chloride infusion to reach a final concentration of 100mg/L. The following storage conditions were tested: (i) 4(o)C in the refrigerator; (ii) 20(o)C under room light exposure and light protection; and (iii) outdoor temperature with sunlight exposure. Moreover, stress testing was performed on drug substance at 20(o)C under ultraviolet (UV) radiation (365 nm). A stability-indicating high-performance liquid chromatography (HPLC) method with UV detection was developed for this analysis. Precision was below 4% and accuracy ranged from 97 to 102%. The lower limit of quantitation was 0.1mg/L. The degradation products produced after UV light exposure were detected upon further analysis by mass spectrometry detection. The stability of temsirolimus is light and temperature dependent. After storage at 20(o)C with room light exposure, the rate of degradation was around 0.25%/h; after 1 day, 92.5% of the initial temsirolimus concentration was recovered. When protected from light, at 4 and 20(o)C, losses were decelerated; the decrease in drug concentration was 1.0 and 1.56% per day, respectively. Under daylight exposure, a substantial decrease in drug concentration was observed; after 1h, losses were higher than 10%. Exposed to UV light, half of the drug was lost after 45 min. In conclusion, temsirolimus 100mg/L in infusion polypropylene bags containing 0.9% sodium chloride was chemically stable when protected from light for 4 and 3 days at 4 and 20(o)C, respectively.

Stability of the ready-to-use solutions of eribulin for intravenous infusion.

A simple HPLC-UV method was developed to determine the stability of ready-to-use eribulin solutions under different storage conditions. The developed method was validated with respect to linearity, accuracy, precision and ruggedness. The following admixtures were prepared: 3-mL polypropylene syringes at concentration of 440 µg/mL and multilayer laminate polyolefin containers containing 0.9% sodium chloride (50 mL) at concentrations of 15.4 and 43.3 µg/mL. The open-vial stability of eribulin was also evaluated. The following storage conditions were tested: 4 °C in the refrigerator; 20 °C under room light exposure; and 20 °C with light-protection. The drug was also subjected to stress conditions of hydrolysis, oxidation, photolysis and thermal degradation. The retention time of eribulin was 4.9 min. Admixtures of eribulin solutions in vials, syringes or polyolefin bags at clinically relevant concentrations were physically compatible and chemically stable for at least 14 days at 4 °C in the refrigerator and at 20 °C with or without any protection against light. Degradation was only found to occur under oxidation conditions.

Guidelines for the practical stability studies of anticancer drugs: a European consensus conference.

Stability studies performed by the pharmaceutical industry are only designed to fulfill licensing requirements. Thus, post-dilution or -reconstitution stability data are frequently limited to 24h only for bacteriological reasons regardless of the true chemical stability which could, in many cases, be longer. In practice, the pharmacy-based centralized preparation may require infusions to be made several days in advance to provide, for example, the filling of ambulatory devices for continuous infusions or batch preparations for dose banding. Furthermore, a non-justified limited stability for expensive products is obviously very costly. Thus, there is a compelling need for additional stability data covering practical uses of anticancer drugs. A European conference consensus was held in France, May 2010, under the auspices of the French Society of Oncology Pharmacy (SFPO) to propose adapted rules on stability in practical situations and guidelines to perform corresponding stability studies. For each anticancer drug, considering their therapeutic index, the pharmacokinetics/pharmacodynamics (PK/PD) variability, specific clinical use and risks related to degradation products, the classical limit of 10% of degradation can be inappropriate. Therefore, acceptance limits must be clinically relevant and should be defined for each drug individually. Design of stability studies has to reflect the different needs of the clinical practice (preparation for the week-ends, outpatient transportations, implantable devices, dose banding…). It is essential to use validated stability-indicating methods, separating degradation products being formed in the practical use of the drug. Sequential temperature designs should be encouraged to replicate problems seen in daily practice such as rupture of the cold-chain or temperature-cycling between refrigerated storage and ambient in-use conditions. Stressed conditions are recommended to evaluate not only the role of classical variables (pH, temperature, light) but also the mechanical stress. Physical stability such as particles' formation should be systematically evaluated. The consensus conference focused on the need to perform more studies on the stability of biotherapies, including a minimum of three complementary separating methods and a careful evaluation of submicron aggregates. The determination of the biological activity of proteins could be also useful. A guideline on the practical stability of anticancer drugs is proposed to cover current clinical and pharmaceutical practice. It should contribute to improved security of use, optimization of centralized handling and reduced costs. Finally, we have attempted to establish a new drug stability paradigm based on practical clinical needs, to complement regulatory guidelines which are essentially orientated to the stability of manufactured drugs.

Stability of amphotericin B and nystatin in antifungal mouthrinses containing sodium hydrogen carbonate.

Amphotericin B and nystatin are two polyene antibiotics that are potent antifungal agents. These drugs are active against most pathogenic fungi like Aspergillus and Candida. Mouthrinses containing these drugs are used for preventive and curative treatment of fungal infections like oral candidiasis, which can cause multiple diseases in cancer patients. Because there were no marketed antifungal mouthrinses available, their preparations were performed at the hospital and town pharmacies. To date, there are no data available on the stability of both these drugs in the form of mouthrinses. Therefore, each mouthrinse had to be prepared extemporaneously. The aim of this study was to investigate the stability of amphotericin B (Fungizone) and nystatin (Mycostatine) in the form of mouthrinses containing 1.4% sodium hydrogen carbonate. The stability of these solutions was tested at different temperatures (4-37 degrees C) with or without electric- or sunlight exposure and in two types of containers (glass and polypropylene) over a 15-day period. The admixtures were also monitored for colour change and pH. Amphotericin B and nystatin were quantified by high-performance liquid chromatography. At 4 degrees C, amphotericin B and nystatin were stable for 15 days in polypropylene. When stored in polypropylene at room temperature, with or without light protection, amphotericin B and nystatin were stable for 3 and 4 days, respectively.

Bayesian estimate of vinorelbine pharmacokinetic parameters in elderly patients with advanced metastatic cancer.

The objective of the present study was to determine the pharmacokinetic profile of vinorelbine in patients 65 years or older with metastatic cancer in progression. Twelve patients were enrolled in this study. Vinorelbine was administered by a 10-min continuous infusion at a dose of 20-30 mg/m2 through a central venous catheter. Chemotherapy was repeated weekly. A total of 46 courses of vinorelbine was studied. Each patient underwent pharmacokinetic evaluation during the first cycle of treatment. Toxicity evaluation was carried out before each course of chemotherapy. Plasma vinorelbine determinations were performed by high-performance liquid chromatography with spectrofluorometric detection. A Bayesian estimation of individual pharmacokinetic parameters was carried out using the nonlinear mixed-effect modeling approach as implemented in the NONMEM computer program. An open three-compartment pharmacokinetic model with a zero order input rate was used to describe the kinetics of vinorelbine. Area under the plasma-concentration time curve (AUC) normalized to a 30 mg/m2 administered dose averaged 0.89 mg/liter x h (coefficient of variation = 23.7%). The total plasma clearance averaged 0.93 liter/h/kg (0.61-1.83 liter/h/kg; coefficient of variation = 38.6%). The elimination half-life was 38.1 +/- 5.8 h. A high correlation was found between patient age and total clearance (r = -0.8; P < 0.001). The main hematological toxicity observed was anemia in 11 patients. Neutropenia occurred in 50% of patients. Significant correlations were found between AUC and the decrease in the hemoglobin level (r = 0.60) and between AUC and the decrease in the neutrophil count (r = 0.66). Thrombocytopenia was observed in only one patient. In conclusion, the age-related decrease in clearance found in this study supports the design of a Phase I study of vinorelbine in patients older than 65 years or perhaps 70 years.

A phase I and pharmacokinetic study of melphalan using a 24-hour continuous infusion in patients with advanced malignancies.

The objectives of the present study were to determine the following: (a) the maximum tolerated dose (MTD) of melphalan using a 24-h continuous infusion; (b) the clinical toxicity; and (c) the pharmacokinetic characteristics of melphalan at each dose level. Twenty-one patients with refractory solid tumors were enrolled in the study. Melphalan, packaged in 3% sodium chloride, was administered i.v. over a 24-h period. Patients were assigned to one of three escalating dose levels of melphalan: (a) 20 mg/m2 (n = 5); (b) 30 mg/m2 (n = 7); and (c) 40 mg/m2 (n = 6). Each patient underwent pharmacokinetic evaluation during the first cycle of treatment. Melphalan concentrations in plasma were determined by high-performance liquid chromatography. Toxicity was evaluated after each course of chemotherapy. All of the patients were assessable for toxicity and pharmacokinetics, and 20 patients were assessable for response analysis. A total of 50 courses of melphalan was studied. The MTD was 30 mg/m2. The dose-limiting toxicity was neutropenia and thrombocytopenia. Hematotoxicity was reversible (nadir, 14-15 days; recovery, 3.5 and 12.5 days for 30 and 40 mg/m2, respectively), cumulative, and related to the administered dose and to the history of previous therapy. There were six episodes of neutropenic sepsis. Individual pharmacokinetic parameters were estimated using a Bayesian approach and linear elimination kinetics. Data were compatible with a one-compartment model. Relationships have been found between the area under the plasma concentration-time curve and doses and between Css and doses. Moreover, clearance, t1/2 elimination, and volume of distribution did not change statistically with dose, which suggests linear kinetics. Two partial responses were observed in patients with ovarian carcinoma or adenocarcinoma of unknown primary origin, and another patient had stabilization disease. In conclusion, melphalan MTD was determined to be 30 mg/m2 when administered as a 24-h infusion. Hematological toxicity was the dose-limiting toxicity. The most important nonhematological toxicity encountered was nausea and vomiting. The recommended dose for Phase II studies was 30 mg/m2.

In vitro modulation of doxorubicin and docetaxel antitumoral activity by methyl-beta-cyclodextrin.

Methyl-beta-cyclodextrin (MEBCD) was investigated for its effect on the antitumoral activity of various antineoplastic agents (doxorubicin (DOX), docetaxel (DXL), 5-fluorouracil (5-FU) and cisplatin (CDDP)) in three different human parental sensitive cancer cell lines (K562 S, MCF7 S and A2780 S) and their multidrug resistant variant sublines (K562 R, MCF7 R and A2780 R). At non-cytotoxic concentrations, MEBCD was able to increase significantly DOX and DXL cytotoxic activity in all the cell lines tested. The sensitisation ratios (IC50 drug control/IC50 drug-MEBCD treated) ranged from 3l1 to 14.3. Moreover, intracellular DOX accumulation, determined by high-performance liquid chromatography, was also increased when cells were treated with MEBCD combined with DOX (approximately 2-3 fold). The effects of MEBCD in resistant sublines were greater than in their parental sensitive cell lines. Other experiments demonstrated that the action of the MEBCD was independent of DOX. These data provided a basis for the potential therapeutic application of MEBCD in cancer therapy.

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.

Salivary and plasma pharmacokinetics of topotecan in patients with metastatic epithelial ovarian cancer.

The comparative saliva/plasma pharmacokinetics of topotecan were investigated in 13 patients with metastatic epithelial ovarian cancer receiving topotecan (30-min intravenous (i.v.) infusion) on a five consecutive day schedule every 3 weeks. During the first and the second courses of treatment, each patient underwent pharmacokinetic evaluation. Quantitation of the total topotecan (lactone plus carboxylate form) was assessed by a highly specific high-performance liquid chromatographic (HPLC) method. Large patient-to-patient variations in the plasma and saliva concentrations were observed. Plasma and saliva pharmacokinetics could be described using a biexponential pattern. From the saliva data, the half-life of the terminal part of the curve was 2.64 h, it was of the same order of magnitude as the topotecan elimination half-life determined from the plasma data, 3.18 h. Topotecan concentrations were higher in the saliva than in the plasma, the saliva/plasma concentration ratio averaged 2.31 and the ratio area under the parotid saliva (AUC(s)) over plasma (AUC(p)) concentration-time curve (AUC(s)/AUC(p)) averaged 2.11. For each individual, a significant relationship was found between topotecan concentrations in the saliva and in the plasma, the coefficients of correlation ranged from 0.75 to 0.92 according to the patient. Myelosuppression, especially granulocytopenia was the most frequent toxicity encountered during the trial. The percent decrease in the leucocyte count, absolute neutrophil count and platelet count were related to the AUCp/day using sigmoidal E(max) models. The high values of the Hill constant found reflect the very steep AUC-haematoxicity relationship observed. In most cases, abdominal pain occurred in patients presenting high saliva concentrations. One patient with high salivary concentrations (mean S/P ratio=4.60) had grade 1 mucositis. In conclusion, the concentration of topotecan in saliva appeared to be useful as an indirect, non-invasive estimation of the levels of topotecan in the plasma; thus, saliva concentrations could be a good predictor of the behaviour of topotecan in the body.

Influence of the schedule of exposure on the cytotoxic effect of melphalan on human 8226 and A2780 cells.

Melphalan was investigated for antitumoral activity using two schedules of exposure (solid versus sequential exposure) in two human cancer cell lines (8226 and A2780). Sequential exposure of melphalan was more effective than solid exposure at the same total dose. The IC50 values averaged 8.2 (solid exposure) and 0.16 microgram/ml (sequential exposure) for 8226 cells (myeloma), and 7.5 (solid) and 0.53 microgram/ml (sequential) for A2780 cells (ovarian carcinoma). Intracellular melphalan accumulation, determined by high-performance liquid chromatography, showed that the area under the intracellular concentration of melphalan versus time curve (between 0 and 30 h) was significantly higher after sequential doses (9.4 micrograms/ml x h) than after solid dose (6.6 micrograms/ml x h). Moreover, intracellular/extracellular concentration ratios indicated that melphalan uptake followed a passive transport system. The increase of both duration of exposure (11 h after solid exposure versus 20 h after sequential doses) and intracellular concentrations 5-6 h after the beginning of the experiment (approximately 3 times higher after sequential doses) indicate sequential administration of melphalan could be more effective than solid exposure.

In vitro schedule-dependent interaction between paclitaxel and vinorelbine in A2780 parental and multidrug-resistant human ovarian cancer cell lines.

Paclitaxel, a taxane, and vinorelbine, a semisynthetic vinca alkaloid drug, have tubulin as their common intracellular target but inhibit growth by acting with opposed mechanisms of action and binding to different sites. The purpose of this study was to evaluate in vitro the cytotoxicity of these two drugs as single agents, in combination and in sequence, against a human carcinoma ovarian cell line A2780S and its doxorubicin-resistant subline A2780R. The cell growth inhibitions were determined by the MTT assay. The cytotoxic effect of drug combinations at the IC50 level were analysed by the isobologram method of Steel and Peckham. On simultaneous exposure to paclitaxel and vinorelbine, synergistic effects were observed in A2780S and A2780R cell lines. On sequential exposure to paclitaxel first followed by vinorelbine or vice versa, a strong antagonistic interaction was observed. These data demonstrate that the interactions of vinorelbine and paclitaxel are highly schedule-dependent. These findings could have implications for the design of further clinical protocols and suggest that the simultaneous administration of the two agents may be the most suitable sequence while sequential administration may be avoided. Further preclinical and clinical studies are required to elucidate the relationship between vinorelbine and paclitaxel with regard to both anti-tumor activity and toxicity.

Combination paclitaxel and vinorelbine therapy: in vitro cytotoxic interactions and dose-escalation study in breast cancer patients previously exposed to anthracyclines.

The objectives of the present study were first to analyse the in vitro cytotoxic interactions between paclitaxel and vinorelbine in order to approach the optimal clinical scheduling in cancer patients, and second to determine the maximum-tolerated doses of this combination without haematopoietic growth factor in breast cancer patients previously exposed to anthracyclines. The in vitro cytotoxicity of paclitaxel and vinorelbine alone, in combination and in sequence, was evaluated against the established human doxorubicin-resistant MCF7 (MCF7-R) breast carcinoma cell line using the standard isobologram methodology. Regarding the simultaneous exposure to vinorelbine and paclitaxel, the combined data points fell mainly on the left side of the envelope of additivity suggesting a synergistic interaction. Conversely the representative isobologram of MCF7-R cells for sequential exposure to vinorelbine followed by paclitaxel or paclitaxel followed by vinorelbine indicated antagonism. These results prompted us to perform a trial of paclitaxel/vinorelbine combination using the administration of these drugs on the same day directly one after the other. The dose-escalation trial included 20 women with metastatic breast cancer who were treated by paclitaxel every 3 weeks (135 mg/m2 starting dose) with 20 mg/m2 steps in subsequent cohorts of patients and vinorelbine (30 mg/m2 fixed dose). Patients were treated every 21 days. A total of 91 courses of therapy were administered to patients at three dose levels. Neutropenic fever was the dose-limiting toxicity at level 3 (paclitaxel 175 mg/m2). Other significant toxicities included sensory neuropathy, myalgias and fatigue. We conclude that paclitaxel 155 mg/m2 and vinorelbine 30 mg/m2 administered directly one after the other on the same day, every 21 days, are the doses recommended for further study.

Methyl-beta-cyclodextrin in HL-60 parental and multidrug-resistant cancer cell lines: effect on the cytotoxic activity and intracellular accumulation of doxorubicin.

The purpose of this work was to determine the role of methyl-beta-cyclodextrin (MEBCD) in combination with doxorubicin (DOX) on the cellular proliferation of a sensitive parental and a multidrug-resistant human cancer cell line (HL-60 S and HL-60 R) and to study the effect of MEBCD on DOX intracellular accumulation. The cytotoxicity of DOX at five concentrations (50-50,000 nM) was evaluated with or without the coadministration of four fixed noncytotoxic concentrations of MEBCD (100, 200, 500, and 1,000 microM). Intracellular DOX concentrations were determined by a high-performance liquid chromatography (HPLC) method with fluorescence detection. MEBCD applied at 500 and 1000 microM in combination with doxorubicin (DOX) significantly potentiated the activity of DOX used alone on both sensitive and multidrug-resistant cell lines; 50% growth-inhibitory (IC50) ratios (IC50 MEBCD-DOX/IC50 DOX) were about 3:4 and 1.6:4 for HL-60 S and HL-60 R, respectively. Moreover, intracellular DOX accumulation, determined by HPLC during 6 h of drug exposure, was about 2-4 times higher for cells treated with MEBCD in combination with DOX than in those treated with DOX alone. Similar results were obtained using other paired MCF 7 sensitive and resistant cell lines. Correlation between these results and an MEBCD-cell membrane interaction was discussed. These initial data provide a basis for the potential therapeutic application of MEMBCD in cancer therapy.

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.

Population pharmacokinetics of topotecan: intraindividual variability in total drug.

The inter- and intraindividual variabilities in topotecan clearance (CL) were explored using a population pharmacokinetic approach. Total (lactone + hydroxy acid) topotecan plasma concentrations were obtained in 31 women with metastatic epithelial ovarian cancer treated by the 30-min intravenous infusion on 5 subsequent days. The data corresponding to three occasions (days 1 and 5 of cycle 1, and day 1 of cycle 2), were analyzed using the nonlinear mixed effect model program. A large interindividual variability was observed, with CL varying from 9.1 to 42.51 per hour (mean 21.0). Topotecan CL was related to serum creatinine level, and age. A close relationship was also observed between topotecan CL and creatinine clearance. Intraindividual variability both within cycle 1 and between the two first cycles was limited, with a mean variation of -2+/-17%, and + 5+/-20%, respectively. A limited sampling strategy using Bayesian estimation based on two samples (5 min before the end of the 30-min infusion, and 4 h after the end of infusion) was developed. The results of this study combine relationships between topotecan pharmacokinetic parameters and patient covariates that may be useful for a priori dose adjustment, and convenient sampling procedure that can be used for further studies and drug monitoring.

Pharmaco-economic study of intensive chemotherapy with peripheral blood progenitor cell support for advanced breast cancer.

Patients with high-risk breast cancer may benefit from dose-escalated chemotherapy. The rationale for high-dose chemotherapy with stem-cell rescue (HDC-SCR) in breast cancer is based on the principles of dose response and dose intensity. However, several results of properly randomized and prospective studies are necessary to determine the interest of HDC-SCR. The objective of this study, realised in the Anticancer Center of Montpellier, was to evaluate the cost of this type of transplantation. In this retrospective study, we analysed 30 patients treated for an advanced breast cancer between October 1995 and June 1998. We collected the data from the induction chemotherapy cycle (followed by cytapheresis) to the end of the hospitalisation for autograft. The mean total cost was US $25,845 per patient: US $6453 for drugs, US $4720 for transfusions, US $1865 for laboratory services and blood tests, US $5585 for staff pay, US $774 for material, US $1211 for administration cost, US $1111 for logistic cost, US $998 for structure cost and US$1578 for other. Antibiotics, granulocyte-colony stimulating factor, chemotherapy, transfusions and nutrition represent respectively 18% (US $1962), 14% (US $1590), 13% (US $1437), 42% (US $4720), 11% (US $1191) of the medication and blood products cost. The results of this study may help in identifying targets for cost reduction.

Pharmacokinetics of high-dose intravenous melphalan in patients undergoing peripheral blood hematopoietic progenitor-cell transplantation.

The pharmacokinetics of melphalan following high-dose (140 mg/m2) i.v. administration were determined in 20 patients with advanced malignancies undergoing peripheral blood hematopoietic progenitor-cell transplantation. Melphalan was assayed in plasma by a specific HPLC method with UV detection. Plasma levels of melphalan declined in a biexponential fashion with a mean terminal half-life of 83 minutes (range 52-168 minutes). Estimated peak plasma concentrations ranged from 1.65 to 14.5 micrograms/ml. Plasma levels were lower than the limit of quantitation of the method used (20 ng/ml) 24 hours after drug administration. The average volume of distribution and total clearance were 317 ml/min/m2 (range 127-797 ml/min/m2) and 37.9 l/m2 (range 15.4-108 l/m2), respectively. These parameters are similar to those reported in the literature. A weak correlation was found between total clearance of melphalan and creatinine clearance (p < 0.05). No relationship between the pharmacokinetics of melphalan and myelosuppression and non-hematologic toxicities was recovered. This pharmacokinetic study indicates that on the assumption that there is no more circulating melphalan after seven elimination half-lives, it may be possible to reinfuse autologous PBPC 10-20 hours after melphalan administration.