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Background A multicenter phase I/II trial of vinflunine administered in combination with cisplatin at 80 mg/m2 was conducted in order to determine the dose-limiting toxicities, the maximum tolerated dose, and the recommended dose of the combination. An eventual mutual pharmacokinetic drug-drug interaction when vinflunine and cisplatin were coadministered was also evaluated. The study was also intended to define the response rate of vinflunine in combination with cisplatin as first-line chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC) at the recommended dose. Patients and Methods Patients were required to have a histologically confirmed diagnosis of NSCLC not amenable to curable treatment or stage IV disease. Patients may have had previous surgery for NSCLC but were to be chemonaive and have at least 1 bidimensional measurable lesion outside an irradiated area. Results The recommended dose was established at cisplatin 80 mg/m2 combined with vinflunine 320 mg/m2. No unexpected adverse events were seen. Pharmacokinetic analysis supported the absence of mutual pharmacokinetic interaction when vinflunine and cisplatin are given in combination. Treatment of 53 patients at this recommended dose demonstrated a tumor response rate of 32.1% in the intent-to-treat population; disease control was achieved in 79.2% of the patients. The median progression-free survival and overall survival were estimated at 5 months and 10.4 months, respectively, and the 1-year survival rate was 43.4%. Conclusion These results place the vinflunine/cisplatin combination among the most active doublets in this treatment setting and warrant further development in phase III trials of first-line treatment of patients with advanced metastatic NSCLC.

The biotransformation of vinorelbine (VRL), an anti-neoplastic vinca-alkaloid derivate already marketed for nonsmall cell lung cancer and advanced breast cancer as an i.v. form and currently registered in several countries as an oral form, was investigated in human. Biological specimen from several human sources constituted the material for the metabolic identification in human. An isocratic liquid chromatographic system composed of 40 mM ammonium acetate (pH 3) and acetonitrile was used for separation of the potential metabolites of VRL. Tandem mass spectrometry with positive electrospray ionisation was used to enable the structural identification of the metabolites. A total of 17 metabolites (12 directly obtained from VRL and 5 involving sequential step pathways) were characterised with proposed structures for most of the metabolites. All metabolites went through phase I reactions by the way of deacetylation, dealkylation, oxidation and hydroxylation. No conjugates were observed. Despite the high number of metabolites quantified, VRL was the major compound observed whatever the matrix. Most of the metabolites rapidly disappeared from blood, except 4-O-deacetyl vinorelbine which was slowly cleared. Most of the enzymatic pathways involved in the metabolites strongly suggested the major role of cytochrome P450 in the biotransformation of vinorelbine.

The lack of a therapeutic effect or unsupportable side-effects can lead to substitution of one antidepressant by another. The present study investigated potential modifications to the pharmacokinetic profile of milnacipran at steady-state when it is substituted for fluoxetine without any washout period. The open-label, multiple dose, three-period study was carried out in 12 evaluable healthy volunteers. A reference period (period 1) comprising a 3.5-day treatment with milnacipran at 50 mg b.i.d. was followed, after a 5-10-day washout, by 3 weeks of administration of 20 mg fluoxetine once daily (period 2), immediately followed by a further 3.5 days of administration of milnacipran at 50 mg b.i.d. (period 3). Blood samples collected at each period were analysed for milnacipran, N-dealkyl milnacipran, fluoxetine and norfluoxetine. Potential drug-drug interactions were evaluated by comparing milnacipran pharmacokinetic parameters between periods 1 and 3. A steady-state of fluoxetine and its metabolite was effectively reached by the end of the 3-week period. A steady-state of milnacipran was reached on day 2 of both periods 1 and 3. Trough concentrations of milnacipran were 66 and 65 ng/ml before and after the fluoxetine administration period, respectively. C max values were 226 and 248 ng/ml. When comparing the kinetic parameters of milnacipran before and after fluoxetine treatment, all the 90% confidence intervals were in the 20% range. No significant difference in the adverse events of milnacipran was observed before or after fluoxetine administration.

Milnacipran is an antidepressant drug belonging to the class of serotonin and noradrenaline reuptake inhibitors. A sensitive high performance liquid chromatographic during the development method coupled with a fluorimetric detection was set up, validated and then used routinely of the drug. After liquid-liquid extraction, milnacipran and its internal standard were analyzed by reversed-phase liquid chromatography (LC). The drug was derivatized with fluorescamine for fluorescence detection. The identity of the liquid chromatography peaks was controlled using mass spectrometry. The assay linearity was validated up to 1000 ng/ml. The limit of quantification was set at 5 ng/ml. Precision values (relative standard deviations) were lower than 5.4%, whereas the mean accuracy was higher than 95%. The extraction recoveries were higher than 70% for both milnacipran and the internal standard. In clinics, the LC-fluorescence method was routinely used to investigate the pharmacokinetics of milnacipran in patients and proved to be robust and capable of quantifying milnacipran in plasma for at least 36 h (four- to five-fold the elimination half-life).

The majority of cancer-related deaths are attributed to lung carcinoma. Age increases this incidence, which is also likely associated with physiologic modifications that affect drug pharmacokinetics and metabolism. Therefore, knowledge of pharmacokinetics in elderly patients is one of the major factors in deciding whether or not to reduce the dose to prevent toxicity. This phase II study was aimed at evaluating the influence of age on oral vinorelbine pharmacokinetics in elderly patients with non–small-cell lung cancer (NSCLC). Inclusion criteria were > 70 years of age; histologically or cytologically proven NSCLC; inoperable stage IIIB, IV, or delayed relapse of any stage becoming unresectable; Karnofsky performance status > 80%; and normal hematology and biochemistry. Blood-limited sampling at intervals of 1.5, 3, and 24 hours after dosing was performed during the first administration of oral vinorelbine at 60 mg/m 2 . Bayesian pharmacokinetic parameters were calculated through previously published nonlinear mixed-effect modeling (NONMEM), and compared with a reference population of 52 patients (age, 56 years ± 12) selected from vinorelbine pharmacokinetic database. There were 48 patients evaluable for pharmacokinetics out of the 52 elderly patients enrolled (age, 74 years ± 3). There was no difference between pharmacokinetic parameters, including the bioavailability factor evaluated by NONMEM, even without intravenous administration, and a similar interindividual variability (32%- 33%) was observed between the 2 groups. Furthermore, no correlation between age (range, 31-82 years) and oral vinorelbine total clearance was observed in 100 patients pooled together. Therefore, no requirement for oral vinorelbine dose reduction was suggested from a pharmacokinetic standpoint.

Objectives. To develop a population pharmacokinetic (PK) model for simultaneous analysis of oral and intravenous data, to compare the variability between the two routes of administration of vinorelbine, to search for the main patient characteristics that explain this variability, and to estimate the mean population bioavailability of oral vinorelbine. Patients and methods. A PK model was developed from 175 phase I/II patients (419 courses) treated by intravenous (20–45 mg/m2) and/or oral (60–100 mg/m2) vinorelbine given as monotherapy. Oral and intravenous PK data were simultaneously fitted using the NONMEM program, allowing the estimation of oral PK parameters such as the bioavailability factor in patients who received only the oral formulation. Covariates included demographic characteristics, biological markers, hematological parameters, liver metastases, early vomiting, and food intake. The population covariate model was developed from rich sampling data (n=187 phase I courses) and then assessed from sparse sampling data (n=232 phase II courses). Results. A three-compartment model best described the combined oral/intravenous blood concentration-time data. The mean absolute bioavailability was 36%, with moderate interindividual (CV=20%) and intraindividual (CV=19%) variability. Bayesian clearance was accurately estimated in 180 of 187 patients. The clearance of oral and intravenous vinorelbine showed comparable variability at usual doses (25–30 mg/m2 intravenous; CV=26%; 60–80 mg/m2 oral, CV=33%) and was moderately increased when including maximum tolerated doses (20–45 mg/m2 intravenous, CV=27%; 60-100 mg/m2 oral, CV=36%). Several relevant covariate relationships influencing the total body clearance of vinorelbine were independent of the route of administration: body surface area (proportional relationship), platelet count above 400×109/l (negative correlation), creatinine clearance (positive correlation), and elevated transaminases (negative correlation). Food intake induced a lag time in the absorption of oral vinorelbine. A weak and poorly estimated relationship was observed between elevated alkaline phosphatase levels and bioavailability, although hepatic markers such as GGT, LDH, total protein, and liver metastases and age had no effect on vinorelbine pharmacokinetics. Conclusions. By means of the simultaneous analysis of oral and intravenous data the bioavailability (F=36%) and its associated variability were estimated. At usual doses similar levels of variability were observed between oral and intravenous routes. As a result of the identification of covariates from phase I data and their confirmation from phase II data further explorations based on limited sampling strategies are now possible. The use of a simultaneous oral/intravenous model allows a better characterization of the PK profile of vinorelbine after administration by either vascular or oral route

Milnacipran is a dual-action antidepressant drug with equivalent inhibitory action at noradrenaline and serotonin neuronal reuptake systems. This dual action has been demonstrated in vitro and in vivo in experimental animals, and ex vivo in man. Milnacipran has no relevant affinity for any neurotransmitter receptor studied, in particular postsynaptic adrenergic, muscarinic and histamine receptors, and is therefore expected to be devoid of the prominent side-effects of many earlier antidepressants. Studies in human volunteers have not demonstrated any impact of milnacipran on cognitive function, consistent with its lack of anticholinergic properties. These pharmacodynamic properties are well preserved in vivo in humans, because milnacipran is only metabolized to a limited extent, and therefore circulates in the body principally as the unchanged parent drug, which is the only pharmacologically active compound at clinical doses. The pharmacokinetic profile of milnacipran is characterized by rapid absorption, high bioavailability, low protein binding, and rapid elimination, both by hepatic glucuronidation and renal excretion. This gives milnacipran certain pharmacokinetic advantages, such as low inter-individual variation in plasma levels, low potential for drug interactions, and limited impact on hepatic cytochrome P450 systems. These pharmacokinetic properties differentiate milnacipran from most other antidepressant drugs and contribute to the good safety profile of milnacipran and allow it to be used simply and flexibly in clinical practice.

Aims a) To characterize the pharmacokinetics of intravenous vinorelbine, b) to use a population analysis for the identification of patient covariates that might appreciably influence its disposition and c) to define a limited sampling strategy for further Bayesian estimation of individual pharmacokinetic parameters. Methods All data were collected from 64 patients (99 courses) entered in three different phase 1 trials that have been previously reported. All patients received vinorelbine as a 20 min infusion with dose levels ranging from 20-45 mg m 2 . The population pharmacokinetic model was built in a sequential manner on a subset of two-thirds of the data, starting with a covariate-free model then progressing to a covariate model using the nonlinear-mixed effect methodology. The remaining one-third of the data were used to validate several sparse sampling designs. Results A linear three-compartment model characterized vinorelbine blood concentrations (n = 1228). Two primary pharmacokinetic parameters (total clearance and volume of distribution) were related to various combinations of covariates. The relationship for total clearance (CL total (1 h -1 ) = 29.2 × BSA × (1 - 0.0090 Plt) + 6.7 × Wt/Cr s ) was dependent on the patient's body surface area (BSA), weight (Wt), serum creatinine (Cr s ) and platelet count before administration (Plt). The optimal limited sampling strategy consisted of a combination of three measured blood concentrations; the first immediately before the end of infusion or 20 min later, the second at either 1 h, 3 h or 6 h and the third at 24 h after drug administration. Conclusions A population pharmacokinetic model and a limited sampling strategy for intravenous vinorelbine have been developed. This is the first population analysis performed on the basis of a large phase I database that has identified clinical covariates influencing the disposition of i.v. vinorelbine. The model can be used to obtain accurate Bayesian estimates of pharmacokinetic parameters in situations where extensive pharmacokinetic sampling is not feasable.

Background: Vinorelbine is a vinca alkaloid obtained by hemisynthesis, which makes the molecule more lipophilic than the other vincas. An injectable formulation is already marketed for the treatment of non small cell lung cancer (NSCLC) and advanced breast cancer (ABC). A new oral form has been developed and its file registration is being submitted. As part of its development, a clinical study was conducted to determine the absolute bioavailability and pharmacokinetics of oral vinorelbine administered as softgel capsules, and to evaluate its safety profile compared with intravenous administration. Patients and methods: Thirty-two patients with solid tumours were included in the study. Patients lasted and were randomised to receive vinorelbine on day 1, either as a 20 minute intravenous (i.v.) infusion of 25 mg/m 2 or as softgel capsules at a dose of 80 mg/m 2 . Patients were treated with the alternate route after a one week wash-out period. Blood and urine samples for pharmacokinetic analysis were collected during each vinorelbine administration. Safety was assessed after each administration using the CALGB/expanded CTC classification. Results: Twenty-four patients were eligible for pharmacokinetic evaluation. Oral vinorelbine was rapidly absorbed at 80 mg/m 2 (T max 1.4 ± 0.7 h) and showed a bioavailability of 43 ± 14, and close to 40% based on AUC last and AUC inf , respectively. A bioequivalence analysis was conducted on dosage-normalised blood exposures. Equivalence was demonstrated between 80 mg/m 2 oral and 30 mg/m 2 i.v., and between 60 mg/m 2 oral and 25 mg/m 2 i.v. The inter-individual variability was equivalent for both routes (CV: 38% and 39% for oral and i.v., respectively). A correlation was found in both methods between AUC last and % nadir variation in white blood cells (WBC) and polymorphonuclears (PMN). More cases of neutropenia (all grades pooled), leucopenia (grades 3-4 only) and nausea (grades 2-3) were induced by 80 mg/m 2 oral vinorelbine than by 25 mg/m 2 i.v. The greatest intensity of these effects, following oral administration, probably reflects the higher, observed drug exposure. Conclusion: At therapeutic dosage levels, pharmacokinetic behaviour and safety profiles were similar for both routes. The absolute bioavailability of the oral vinorelbine (new, soft gelatine capsule) was close to 40%. Inter-individual variability in drug exposure was equivalent in both routes. The pharmacokinetic/pharmacodynamic (PK/PD) relationship in haematological toxicity was independent of the routes of administration. Reliable, corresponding doses between oral and i.v. vinorelbine were established, which will result in bioequivalent AUC.

Vinorelbine is an established treatment for advanced non-small cell lung cancer (NSCLC), both as a single agent and in combination chemotherapy. Recently, an oral form of this agent has been developed. Before accepting an established agent in a different administration form, rigorous testing is required to answer such questions as reliable bioavailability, continued safety and preservation of efficacy. In addition, an oral agent must provide patient convenience and acceptance, while being an economically sound approach. Oral vinorelbine was found to have acceptable and reliable pharmacokinetic profiles at clinically relevant dosage levels. Oral vinorelbine was found to have approximately 40% bioavailability; thus, a dose of 80 mg/m(2) orally is the equivalent of 30 mg/m(2) intravenously, and 60 mg/m(2) orally is the equivalent of 25 mg/m(2) intravenously. Studies also concluded a lack of food effect on the administration of oral vinorelbine. In addition, no drug-drug interactions were found with a variety of commonly used antineoplastic agents.Vinorelbine, either orally or intravenously, has been investigated in randomised phase II trials as a single agent and in combination with cisplatin or carboplatin in patients with NSCLC. In general, response and survival results with oral vinorelbine appeared similar to the intravenous agent. Adverse-effect profiles were also similar for the two formulations. Clearly, the issue of venous irritation does not exist with oral vinorelbine; however, nausea and vomiting were more frequent when vinorelbine was administered orally compared with intravenously when no planned antiemetic therapy is given.

The availability of chemotherapeutic drugs administrable by oral route represents a step forward in the management of cancer patients. Among oral agents, vinorelbine is particularly interesting for its pharmacological characteristics and clinical efficacy. Oral vinorelbine is rapidly absorbed (1.5-3 hours) with an elimination half-life of approximately 40 hours. It shows a low level of binding to plasma proteins (13%), is highly bound to platelets (78%) and has a hepatic metabolism and an absolute bioavailability of 40% with a moderate and similar interpatient variability for the two forms. Food has no influence on the pharmacokinetic profile of oral vinorelbine even if nausea/vomiting is less frequent and less severe in the fed patients than in the fasting patients. Therefore, to ensure patient comfort, it is recommended that oral vinorelbine is administered with a snack. All the metabolites of oral vinorelbine have been identified and, among these, only deacetyl-vinorelbine presented activity demonstrating that for both oral and intravenous (i.v.) routes of administration the drug has the same metabolism pattern. Oral vinorelbine is eliminated mainly in a unconjugated form via the bile. In this process, the CYP 3A4 isoform of cytochrome P450 is mostly involved. Absorption of oral vinorelbine is not delayed in elderly patients. After oral administration, blood concentrations of vinorelbine in elderly patients are within the range of values observed in younger patients. The absolute bioavailability is close to 38% in elderly whereas it is close to 40% in younger patients. This difference is not significant. As compared to the intravenous drug, oral vinorelbine demonstrated linear pharmacokinetics as well an absolute bioavailability of approximately 40%, and a reliable dose-correspondence of 80 mg/m2 oral form --> 30 mg/m2 i.v. and 60 mg/m2 oral --> 25 mg/m2 i.v. Therefore, i.v. and oral forms show similar interindividual variability, same metabolism pattern, reproducible intra-patient blood exposure, and same pharmacokinetic-pharmacodynamic relationship. Oral vinorelbine has shown significant activity in advanced non-small cell lung cancer. Given at 60 mg/m2/week for the first 3 administrations and then increased to 80 mg/m2/week achieved the same efficacy as i.v. vinorelbine in terms of progression-free survival, overall survival, objective response. Mild-to-moderate gastrointestinal toxicity, easily manageable with standard treatment was recorded. Reproducible efficacy compared to previously reported results with vinorelbine i.v. Also, in advanced breast cancer, oral vinorelbine has shown significant activity with a good therapeutic index. Albeit no formal comparison between the oral and the intravenous formulations of vinorelbine has been made, however, the oral route seems to offer major advantages to patients who are faced with a clear decrease in the frequency of hospital admissions as compared to that needed to give intravenous chemotherapy.

Despite the large number of antidepressants currently available, it is still necessary to develop new drugs that combine the efficacy of the older antidepressant with improved safety, tolerability and therapeutic profile that will allow them to be used in depressed patients who are elderly or with cardiac, renal or hepatic disease. This article reviews the pharmacokinetic characteristics of the tricyclic antidepressants, the selective serotonin reuptake inhibitors (SSRIs) and more recently introduced antidepressants such as venlafaxine and nefazodone. Milnacipran (Ixel), a novel drug, combines antidepressant efficacy with some unique pharmacokinetic features. A summary of its pharmacokinetic profile shows that milnacipran has a high bioavailability, low plasma protein binding and that it is largely eliminated in the urine as parent drug or as a glucuronide. These features suggest that the likelihood of interactions with other drugs given concurrently is lower than would occur with most second generation antidepressants and the tricyclic antidepressants. Furthermore, studies in patients with liver dysfunction, and in the elderly, suggest that dose adjustment is not necessary when milnacipran is administered to these patients. The decrease in milnacipran elimination is correlated to the degree of renal impairment, allowing adjustment of schedules. In comparison to earlier antidepressants, milnacipran combines efficacy and a relatively low side-effect profile with the added advantage of fewer interactions with drugs that may be given concurrently.

Most antidepressants produce changes in monoamine receptors in brain after chronic administration in animals. The most commonly described alterations are a decreased density and function of β-adrenergic receptors and have been postulated to be the mechanisms by which antidepressants exert their therapeutic effect. Milnacipran (previous name midalcipran) is a new, clinically-effective antidepressant, which inhibits the uptake of both serotonin and noradrenaline but has no affinity for any pre- or postsynaptic receptor studied. When given either orally at 7.5 mg/kg twice daily for 3 days, at 30 mg/kg once daily for 3 weeks, by osmotic mini-pump at 30 mg/kg/day for 27 days, or in drinking water at approximately 15 mg/kg/day for 6 weeks and after a washout period of 24 hr, milnacipran produced no down-regulation of β-adrenoceptors. In addition, there were no alterations of α 1 - or α 2 -adrenoceptors, 5-HT 1 5-HT 2 receptors or benzodiazepine binding sites. Moreover, uptake and accumulation of serotonin and noradrenaline were unmodified. In addition, the potency for milnacipran to inhibit monoamine uptake in vitro in the cortex was not altered in treated rats, compared to control animals. Thus, in spite of its action on both the uptake of serotonin and noradrenaline, milnacipran appears to be without long-term action on β-adrenoceptors or the other receptors studied, suggesting that, at least for this antidepressant, these modifications are not essential for clinical activity.

We studied the pharmacokinetic profile of weekly oral and intravenous vinorelbine in cancer patients with various degrees of hepatic function, and assessed an intra-patient comparison of the pharmacokinetics of i.v. versus oral vinorelbine. in this open-label study, patients were randomised to receive an initial dose of vinorelbine at day 1 by either i.v. or the oral route followed by a second dose on day 8 via the alternative route. A total of 16 patients were included, 12 patients received the planned two administrations. Toxicities were similar for all cohorts and were mainly of haematological and gastrointestinal origin. Pharmacokinetic analysis of both routes did not reveal any differences between cohort I and II. Based on these findings in patients with mild to moderate liver dysfunction no dose modifications of vinorelbine have to be taken into consideration. (C) 2009 Elsevier Ltd. All rights reserved.

Aim: To determine the safe dose range and pharmacokinetics of metronomic oral vinorelbine and obtain preliminary data on biomarkers and efficacy in patients with advanced cancer. Methods: Successive cohorts of patients received escalated doses of oral vinorelbine given thrice a week until disease progression, unacceptable toxicity (UT), or consent withdrawal. UT was any grade 4 toxicity, or grade 2 or 3 toxicity that would result to longer than 2-week break during the first 2 months of treatment. Blood samples were collected for pharmacokinetics and quantification of angiogenesis regulatory proteins. Results: Sixty-two patients (median age, 60 years) enrolled at six dose levels from 20 to 70 mg and received treatment for median 12.25 weeks (range, 2-216+). Unacceptable toxicity occurred in two of six patients treated at 60 mg (leucopenia grade 4 and epistaxis grade 2) and in one at 70 mg (leucopenia grade 2). The upper metronomic dose was 50 mg. Objective antitumor response documented in eight cases and 32% of patients experienced disease stability for minimum 6 months. Three responders (renal cancer, medullary thyroid carcinoma, and Kaposi sarcoma) received nonstop treatment for over 3 years without overt toxicity. Low pretreatment levels of circulating interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor were found predictors of efficacy. Steady-state concentrations of vinorelbine and its active metabolite ranged from 0.5 to 1.5 ng/mL. Conclusions: Metronomic administration of oral vinorelbine is feasible at doses up to 50 mg thrice a week and can yield sustainable antitumor activity without overt toxicity, probably through antiangiogenic mechanism. Further clinical investigation is warranted. (Clin Cancer Res 2009;15(20):6454–61)

This study was conducted to retrospectively compare the area under the curve (AUC) and the total clearance of busulfan (Bu) following oral and intravenous (IV) administrations and to determine which intravenous dose generated equivalent exposure to that of the oral form that has been marketed for decades. Patient pharmacokinetics were assessed at dose 9 during a conditioning regimen for stem-cell transplantation and included data from 277 patients for oral Bu (71 from fixed-dose studies and 206 from studies with dose adjustment allowed) and 120 patients for IV Bu (fixed dose). AUCs were compared between patients with fixed dose of oral Bu (n = 71, 1 mg/kg) and those of IV Bu (n = 120, 0.8 mg/kg). Total clearances were calculated for all 277 patients with oral Bu and compared to those with IV Bu, with the ratio of IV-to-oral clearance representing the absolute bioavailability of the oral form. Oral and IV populations differed on disease-type distribution but presented comparable demography parameters. IV Bu dosing was mostly based on the ideal body weight index while actual body weight or adjusted ideal body weight indexes were mostly used for oral. When normalised to comparable indexes, bioequivalent AUCs were achieved between oral and IV populations. Oral Bu bioavailability was about 80% when calculated from the ratio of IV-to-oral total clearances. This retrospective study carried out on a large set of data showed that similar plasma exposures were achieved with 1.0 mg/kg oral Bu or 0.8 mg/kg IV Bu.

Patient's preference is for oral chemotherapy when both oral and i.v. are available, provided that efficacy is equivalent. Reliable switch from oral to i.v. is possible if correspondence between respective doses has been established. Vinorelbine oral was developed as a line extension of VRL i.v. on the basis that similar AUCs result in similar activities. From a first crossover study on 24 patients receiving VRL 25 mg/m2 i.v. and 80 mg/m2 oral data extrapolation concluded on AUCs bioequivalence between Vinorelbine 30 mg/m2 i.v. and 80 mg/m2 oral. A new trial was performed to support this calculation. In a crossover design study on patients (PS 0-1) with advanced solid tumours (44% breast carcinoma), VRL was administered (30 mg/m2 i.v., 80 mg/m2 oral) with a standard meal and 5-HT3 antagonists, at 2 weeks interval. Pharmacokinetics was performed over 168 h and VRL was measured by LC-MS/MS. Statistics included bioequivalence tests. Forty-eight patients were evaluable for PK: median age 58 years (25-71), PS0/PS1: 20/28, M/F: 11/37. Mean AUCs were 1,230 +/- 290 and 1,216 +/- 521 ng/ml for i.v. and oral, respectively. The confidence interval of the AUC ratio (0.83-1.03) was within the required regulatory range (0.8-1.25) and proved the bioequivalence between the two doses. The absolute bioavailability was 37.8 +/- 16.0%, and close to the value from the first study (40%). Patient tolerability was globally comparable between both forms with no significant difference on either haematological or non-haematological toxicities (grade 3-4). This new study, conducted on a larger population, confirmed the reliable dose correspondence previously established between vinorelbine 80 mg/m2 oral and 30 mg/m2 i.v.

A sensitive high performance liquid chromatographic method was developed and validated for the simultaneous quantification of vinorelbine and its active metabolite, 4-O-deacetyl vinorelbine, in human biological fluids. These two compounds together with vinblastine, used as internal standard, were extracted from blood and urine by a liquid-liquid process using diethyl ether, and followed by a back-extraction in acidic conditions. Then, they were analysed through a cyano column and detected in ultraviolet at 268 nm. The assay linearity was validated up to 2000 ng/ml. The lower limit of quantification was set at 2.5 ng/ml. The between-run precision and accuracy were always higher than 94%. Biological samples were stable when stored at -80 degrees C over 2 years. The long-term reproducibility and the suitability of this analytical method were demonstrated within the last decade through the analysis of about 7000 samples during the clinical development of i.v. and oral formulations of vinorelbine. Because vinorelbine binds mainly to platelets and blood cells and because this binding is rapidly reversible and highly influenced by environmental conditions, drug concentration in plasma may be highly influenced by the sampling conditions and the centrifugation process used to separate blood cells from plasma. Therefore, this method was developed in blood and then used for sample analyses in routine. The major benefit was that it was easy for nurses to directly collect blood instead of plasma and that reduced volume of sampling could be withdrawn from frail patients. Furthermore, the analysis in blood enabled to quantify vinorelbine and 4-O-deacetyl vinorelbine concentrations for a longer period of time, which resulted in a more accurate evaluation of pharmacokinetic parameters.

Objective: To compare the pharmacokinetics of milnacipran in extensive metabolisers (EMs) and poor metabolisers (PMs) of sparteine and mephenytoin, and to assess the influence of multiple administrations of milnacipran on the activity of cytochrome P450 (CYP) isoenzymes through its own metabolism and through various probes, namely CYP2D6 (sparteine/dextromethorphan), CYP2C19 (mephenytoin), CYP1A2 (caffeine) and CYP3A4 (endogenous 6-β-hydroxy-cortisol excretion). Methods: Twenty-five healthy subjects, 12 EMs for both sparteine/dextromethorphan and mephenytoin, nine EMs for mephenytoin and PMs for sparteine/dextromethorphan (PM2D6) and four PMs for mephenytoin and EMs for sparteine/dextromethorphan (PM2C19) were administered milnacipran as a single 50mg capsule on day 1 followed by a 50mg capsule twice daily for 7 days. The pharmacokinetics of milnacipran and its oxidative metabolites were assessed after the first dose (day 1) and after multiple administration (day 8), and were compared for differences between CYP2D6 and CYP2C19 PMs and EMs. Metabolic tests were performed before (day —2), during (days 1 and 8) and after (day 20) milnacipran administration. Results: Milnacipran steady state was rapidly achieved. Metabolism was limited: approximately 50% unchanged drug, 30% as glucuronide and 20% as oxidative metabolite (mainly F2800 the N-dealkyl metabolite). Milnacipran administration to PM2D6 and PM2C19 subjects did not increase parent drug exposure or decrease metabolite exposure. Milnacipran oxidative metabolism is not mediated through CYP2D6 or CYP2C19 polymorphic pathways nor does it significantly interact with CYP1A2, CYP2C19, CYP2D6 or CYP3A4 activities. Conclusion: Limited reciprocal pharmacokinetic interaction between milnacipran and CYP isoenzymes would confer flexibility in the therapeutic use of the drug when combined with antidepressants. Drug-drug interaction risk would be low, even if the combined treatments were likely to inhibit CYP2D6 and CYP2C19 isoenzyme activities.

An IV form of busulfan (IV Bu) has recently become available for high dose conditioning regimen before haematopoietic stem cell transplantation (HSCT). This IV form is expected to reduce the high pharmacokinetic variability exhibited with oral busulfan and as a result, to better target the plasma area under the curve (AUC). Pharmacokinetics (PK) of IV Bu was investigated on 127 adult patients (333 PK administrations) who received 0.8 mg.kg-1 of Bu as a 2-h infusion every 6 h over 4 days, followed by cyclophosphamide (60 mg.kg-1 day-1x2). A retrospective population PK analysis was carried out to search for important predictive factors of IV Bu PK and to develop a limited sampling strategy (LSS) through Bayesian methodology. The analysis was conducted using the Non Linear Mixed Effect methodology and included a validation process on an independent data set. Adjusted Ideal Body Weight (AIBW) and Body Surface Area (BSA) were the best covariates to explain the inter-patient variability. The final inter-patient variability (CV=16%) in IV Bu clearance (Cltot) was estimated close to the intra-patient variability (CV=13%). There was neither age-dependency nor gender effect. IV Bu Cltot was not affected by elevated hepatic enzymes or by co-administration of either fluconazole or acetaminophen, and was not altered in heavily pre-treated or pre-transplanted patients. Normalised Cltot based on either AIBW or BSA was comparable between normal and obese patients (BMI=18-26.9 kg.m-2,26.9 kg.m-2, respectively) whereas significant differences existed when based on either actual (ABW) or ideal body weight (IBW). As a consequence, no dose adjustment is required in obese patients when using a AIBW- or BSA-based dose calculation. A fixed dose of 0.80 mg.kg-1 of AIBW or 29 mg.m-2 of BSA yielded an average AUC of 1,200 microM.min, with 80% of patients within the "therapeutic" AUC range of 900-1,500 microM.min. Alternatively, 0.80 mg.kg-1 based on either ABW or IBW for normal patients and on AIBW for obese patients would achieve the same performance. A limited sampling strategy based on a Bayesian methodology was developed and validated on an independent dataset: AUCs obtained from one to two samplings were demonstrated to be reliably estimated.

A retrospective population pharmacokinetic (PPK) analysis was performed in 24 pediatric patients (PEDS) (0.45-16.7 years old) receiving i.v. busulfan/cyclophosphamide (i.v. Bu/Cy 4) regimen prior to allogeneic hematopoietic stem cell transplantation. I.V. Bu doses were given as a 2-hour infusion every 6 h over 4 days. Initial dosing of i.v. Bu was 1 mg/kg for childrenor =4 years old and 0.8 mg/kg for patients4 years old. Bu plasma concentrations at doses 1, 9 and 13 were analyzed through a multivariate NONMEM analysis. A close log-linear relationship between body weight (BW) and i.v. Bu clearance was demonstrated with no further age-dependency or gender effect. The interpatient coefficient of variation (CV) in Bu clearance significantly decreased from 56% (covariate-free model) to 19% (BW covariate model) and reproducible i.v. Bu exposure between doses was illustrated (intraindividual CV=9%). Based on the PPK model, a novel Bu dosing regimen (ie: doses in mg/kg adjusted to discrete weight categories) for a better AUC targeting was developed by simulation on 1000 patients. Age-based dosing was demonstrated not to be clinically relevant with i.v. Bu. Use of the new BW-based dosing appears to be more appropriate for the PEDS.

As pharmacokinetics represents a bridge between pharmacological concentrations and clinical regimens, the pharmacokinetic exploration of the therapeutic dose range is a major outcome. This study was aimed at assessing pharmacokinetic linearity of i.v. vinorelbine through an open design with intra-patient dose escalation (3 doses/group). Three groups of six patients received either 20-25-30 mg/m2; or 25-30-35 mg/m2; or 30-35-40 mg/m2. The inclusion criteria were: histologically confirmed tumour with at least one assessable target lesion, age 25-75 years, WHO PSor =2, normal haematology and biochemistry, life expectancyor =3 months. The pharmacokinetics was evaluated in both whole blood and plasma over 120 h. Twenty-six patients were recruited and 18 were evaluable for pharmacokinetics. The toxicity consisted in gradeor =3 leucopenia and neutropenia (20% of courses) and two grade 4 constipation with rapid recovery (2/54 courses). Compared to blood, plasma was demonstrated to underestimate the pharmacokinetic parameters. In blood, the drug total clearance was about 0.6 l/h/kg, with minor contribution of renal clearance, steady state volume of distribution close to 13 l/h/kg, and elimination half-life at about 40 h. A pharmacokinetic linearity was demonstrated up to 40 mg/m2, and even up to 45 mg/m2 when pooling data from another study. A pharmacokinetic-pharmacodynamic relationship was evidenced on leucopenia and neutropenia when pooling the data from the two studies.

A new sensitive and specific liquid chromatographic method coupled with tandem mass spectrometric detection was set up and validated for the simultaneous quantitation of vinorelbine, its main metabolite, 4-O-deacetylvinorelbine and two other minor metabolites, 20'-hydroxyvinorelbine and vinorelbine 6'-oxide. All these compounds, including vinblastine (used as internal standard) were deproteinised from blood, plasma and faeces (only diluted in urine), analysed on a cyano column and detected on a Micromass Quattro II system in the positive ion mode after ionisation, using an electrospray ion source. Under tandem mass spectrometry conditions, the specific product ions led one to accurately quantify vinorelbine and its metabolites in all biological fluids. In whole blood, linearity was assessed up to 200 ng/ml for vinorelbine and up to 50 ng/ml for the metabolites. The limit of quantitation was validated at 250 pg/ml for both vinorelbine and 4-O-deacetylvinorelbine. In the other biological media, the linearity was assessed within a same range and the limit of quantitation was adjusted according to the expected concentrations of each compound. This method was initially developed in order to identify the metabolite structures and to elucidate the metabolic pathway of vinorelbine. Thanks to its high sensitivity, this method has enabled the quantitation of vinorelbine and all its metabolites in whole blood over 168 h (i.e., 4-5 elimination half lives) whilst the previous liquid chromatographic methods allowed their measurement for a maximum of 48-72 h. Therefore, using this method has improved the reliability of the pharmacokinetic data analysis of vinorelbine.

The pharmacokinetics of single 50 mg oral and intravenous doses of milnacipran, a new non tricyclic antidepressant drug, were compared in 11 chronic liver impaired (LI) subjects and in 6 control subjects. Hepatic impairments, classified according to the PUGH scale were moderate (1 grade A), intermediate (6 grade B) and severe (4 grade C). Concentrations of unchanged drug and its conjugated form (its main metabolite) were measured in plasma and urines. In control subjects, milnacipran present high absolute bioavailability (mean value of 90%). Around 50% of the dose are excreted in urines as unchanged, while around 14% are excreted as glucuroconjugate. The remaining is composed of free and conjugated phase I inactive metabolites. Administration of milnacipran in LI subjects results in non significant changes in its pharmacokinetics, although its variability is increased. Unchanged drug exposure is not modified in LI subjects, while plasma levels of the conjugate are slightly decreased compared to the control group. This could either be due to a slight reduction in the conjugation process, or to a change in the distribution of the drug as urine excretion of both unchanged and conjugated forms are not modified compared to the control group. A few LI subjects present supra-bioavailability resulting in higher drug exposure after oral administration than after intravenous infusion. These modifications are not clinically relevant as drug exposure of the parent drug is not modified. As the unchanged drug is the only compound responsible for the activity of milnacipran, no dosage adjustment is needed in patients presenting liver impairment.

The P-glycoprotein (P-gp) multidrug transporter is present at the luminal face of the brain capillary endothelial cells that contribute to the blood-brain barrier. To study its role in transendothelial anticancer drug transport, we made use of a co-culture system formed of bovine brain capillary endothelial cells and astrocytes which allows the in vitro maintenance of specialized properties of the brain endothelial cells, including expression of P-gp as assessed by Northern and Western blot analyses. Vinblastine, an anticancer drug substrate for P-gp and known not to enter the brain, was found to be poorly transferred across the endothelial cell monolayer. This low vinblastine transport was however strongly increased in the presence of verapamil, a well known P-gp blocker. Moreover, verapamil was shown to increase the accumulation of the anticancer drug in the brain endothelial cells through inhibition of drug efflux. These results suggest that P-gp activity evidenced in the co-culture model is involved in the low transendothelial transport of vinblastine, thus supporting the conclusion that P-gp expressed at the blood-brain barrier level may prevent xenobiotics, including anticancer drugs, from entering the central nervous system.

Drug transport across the blood-brain barrier (BBB) is a key step in the treatment of cerebral diseases; it is largely dependent on membrane permeability of brain capillary endothelial cells. In order to investigate the functional features of the BBB in vitro, a coculture model of bovine brain capillary endothelial cells and new-born rat astrocytes has been recently established (Dehouck et al, J. Neurochemistry, 54: 1798–1801, 1990). Using this system, we have analysed brain capillary endothelial cell (BCEC) permeability for vinblastine, an anticancer drug substrate for the multidrug transporter P-glycoprotein (P-gp). Vinblastine endothelial permeability coefficient was found to be low, as for various compounds (i.e. inulin, sucrose, sulpiride), known to poorly accumulate in the brain. In the presence of verapamil, a known inhibitor of P-gp function, vinblastine transfer across BCECs was strongly enhanced. These data therefore suggest that BCECs display P-gp activity that is directly involved in low endothelial permeability of anticancer drugs such as vinblastine.

International audience; To determine whether compounds are able to reach the neural microenvironment, a blood-brain barrier (BBB) co-culture model has been recently developed with bovine brain capillary endothelial cells and newborn rat astrocytes. In this study, the permeability of confluent endothelial cells to various compounds and the functional activity of P-glycoprotein (P-gp), an ATP-dependent pump known to efflux drugs from multidrug-resistant tumoral cells, was assessed. The permeability of the lipophilic compounds imipramine and sulpiride differed in relation to their structure. A good correlation was observed with in vivo brain extraction levels. P-gp activity was estimated by measuring the uptake of [3H]vinblastine by the endothelial cells, with or without verapamil, which is known to reverse drug resistance. Intracellular accumulation of the vinca alkaloid was strongly increased after addition of verapamil, suggesting that P-gp is active in these cells. These results provide further support for the use of the co-culture model of bovine brain endothelial cells and rat astrocytes to screen new centrally active drugs.

Milnacipran is a new antidepressant agent selected from a series of cycloproprane derivatives. The aim of this study was to investigate the acute electrophysiological effects and the tolerance of intravenous administration of this drug in 10 patients without any abnormality as shown in an electrophysiological study done for various complaints. Milnacipran was given over a 30-min period at doses of 0.2 mg/kg (2 patients), 0.4 mg/kg (2 patients) and 0.8 mg/kg (6 patients). The most significant alternations observed in this study were increases in heart rate (average of maximal increase: + 19.5% at 50 min, P = 0.06) and systolic blood pressure (average of maximal increase: + 21.5% at 10 min, P

Background: High dose busulfan (BU) in combination with cyclophosphamide (BUCY) is a preferred conditioning regimen for patients with hemoglobinopathies. Recently introduced intravenous BU (IVBU) has decreased intra-and inter-individual variability of BU systemic exposure (AUC) when compared to oral dosing. There are no data available on IVBU pharmacokinetics (PK) in a large group of patients with thalassemia to date. Purpose: to asses the IVBU PK in relation to patient and disease-related (hepatomegaly, blood transfusion, ferritin, liver iron concentration, hepatitis, liver fibrosis) variables and the relationship of BU exposure to toxicities and transplant outcomes in children and young adults given SCT for thalassemia from HLA-matched related donors. Methods: 57 patients with thalassemia major with median age of 9 years (range, 1.6–24) received IVBU (Busilvex, Pierre Fabre Medicament, France) as a part of conditioning regimen between 2006 and 2008. BU doses were based on actual body weight: 34=0.8 mg/kg (n=11) and were given every 6 hours for 4 days. Valproic acid (Depakin) was administered before and during BU treatment as anticonvulsant prophylaxis. Most patients had liver disease and moderate to severe iron overload. Class 1 and class 2 patients (n=24) received IVBU in combination with CY200 ± thiotepa as conditioning regimen. Class 3 patients (n=33) before conditioning with IVBU/CY160 ± thiotepa were given cytoreduction/immunosuppression with hydroxyurea, azathioprine and fludarabine between −45 and −12 days pretransplant. GVHD prophylaxis consisted of CSA+ short MTX. Blood samples were drawn just before and 2h, 4h, and 6h after BU administration following the 1st, 5th, 9th, and 13th doses for PK assessment by HPLC-MS. Dose adjustment (DA) was made at the 3rd dose as needed, to target an AUC range of 900–1350 μol/L/min. The influence of patient and disease-related variables on IVBU PK was investigated by a population PK-based approach using the NONMEM program. Results: PK parameters following the 1st dose are reported in Table. Overall, 58% of patients AUC were within, 37% were below and 5% were above the target range following the 1st dose of IVBU. Dose elevations of 5.2–54% (median, 18.8%) were made in 17 patients and dose reductions of 5–34.2% (median,9.2%) in 19 patients. Following DA 79 % of patients after the 5th and 9th doses and 91 % after the 13th dose reached the target range. The inter-patient variability in IV BU clearance was moderate (CV=19%) and the intra-patient variability was low (CV=7%). Only weight or body surface area significantly explained the PK variability. Fifty three patients had sustained engraftment, 4 had primary (n=2) or secondary (n=2) graft failure. Forty eight (89%) of 54 evaluable patients were complete and 6 (11%) mixed chimeras. One patient had moderate hepatic VOD resolved with supportive care. Seventeen patients developed grade 2–4 acute GVHD. None of patients had seizure within 30 days post-transplant. Grade 1 or 2 ALT/AST increases were observed in 19,3% and 44% of patients and stomatitis/diarrhoea in 47% and 19% of patients respectively. Five patients died. There was no relationship between busulfan exposure and toxicities, engraftment time, chimerism, rejection, GVHD and survival in univariate analysis. No association was found between PK parameters and transplant outcomes in a subgroup of patients (n=19) who never needed DA. This study demonstrates that IVBU in children with thalassemia who have important organ damage due to their disease and treatment is well tolerated with no increase in organ system toxicity. IVBU exposure did not predict rejection, liver VOD or death in patients with thalassemia who received HLA-matched related SCT. AUC, μol/min Css, ng/ml Cmax, ng/ml Cmin, ng/ml Cl, ml/min/kg Vd, L T ½, h Mean ± sd 982± 203 672± 139 1071± 207 239± 72 4.23± 0.95 16.8±6.8 1.8±0.2 Range 630–1621 431–1109 735–1614 101–450 2.31–6.43 7.3–43.6 1.2–2.3

Background: Oral busulfan (Bu) is a standard component of hematopoietic stem cell transplantation (HSCT) regimens in pediatric patients (pts). Bu exposure (AUC) has been correlated with outcomes, thus dose adjustment and therapeutic drug monitoring (TDM) were needed. An IV Bu formulation would allow to target AUC and improve outcomes of HSCT. We previously reported that a new IV Bu fixed dose based on body-weight calculation can successfully target a therapeutic AUC in children without any dose-adjustment and TDM [Vassal G. et al., ASCO2005;# 8535]. We report here the pharmacokinetics (PK) results and clinical outcomes of this cohort. Methods: Children received Bu/Melphalan (Mel, 140 mg/m2) before autologous (auto-, n=27) or Bu/Cyclophosphamide (Cy, 200 mg/kg) before allogeneic (allo-, n=28) HSCT. Donors were mainly HLA-matched sibling (n=22). IV Bu was administered over 2 h at a dose of 1.0 mg/kg, 1.2 mg/kg, 1.1 mg/kg, 0.95 mg/kg, and 0.8 mg/kg for pts with < 9 kg, 9-< 16 kg, 16–23 kg, >23–34 kg, and >34 kg strata of weight, respectively. PK was performed at doses 1, 9 and 13 but no dose adjustment was allowed. Clonazepam was given as seizures prophylaxis. Indications for HSCT were: high risk neuroblastoma (n= 24), Ewing sarcoma (n=3) for auto-HSCT; AML (n= 14), CML (n= 3), ALL (n=1), MDS (n=1), hemoglobinopathy (n=6), and immunodeficiency (n=3) for allo-HSCT. Median age (range) was 4.0 y (0.7-14.9), and 7.2 y (0.3–17.2) for auto- and allo-HSCT, respectively. Results: Bu PK analysis demonstrated that 91% of AUCs were in 900–1500 μM. min range, despite a large variability (CV= 50%) on Bu clearance among dose levels. IVBu based BuMel or BuCy regimens were well tolerated. VOD incidence was 15% (95% CI: 4–33.7%) and 7% (95% CI: 0.9–23.5%) in auto- and allo-HSCT recipients, respectively but none was severe. In all pts neutrophils (> 0.5 x 109/L) and platelets (> 50.0 x 109/L) recovery occurred at the expected time. Donor engraftment was documented in all recipients: 26/28 achieved complete chimerism, and 2/28 were mixed chimeras but had mainly donor cells (> 85%). There was no death at Day +100 post-transplant. One patient died due to chronic GVHD at 13 months. Cumulative incidence of TRM was 0% (auto-HSCT) and 3.8% ± 7.6% (allo-HSCT). Median follow-up was 31.6 months (range 20.1–41.2) and 28.0 months (range 18.2–38.2) after auto- and allo-HSCT, respectively. Event-free and overall survivals were as follows: 59% ± 18% and 70% ± 18%, respectively after auto-HSCT; and 85% ± 13% for both probabilities after allo- HSCT. Conclusions: This new IV Bu fixed dosing can successfully target a therapeutic AUC without any dose-adjustment and TDM and results in a low incidence of transplant-related mortality. Complete chimerism was achieved by 93% of allo-recipients without any case of graft rejection.

In a placebo-controlled double-blind cross-over study, we gave 12 healthy male volunteers placebo or milnacipran orally, such that each volunteer received placebo and two doses of milnacipran. Blood samples taken before and at various times after dosing were analysed for plasma concentrations of unchanged milnacipran and the inhibitory effect of the plasma on the uptake of 3H-5-hydroxytryptamine (5HT) into normal human platelets or of 3H-noradrenaline into rat hypothalamus homogenate. The mean maximal inhibition of 5HT and noradrenaline uptake was correlated with drug dose. The inhibition of 5HT uptake was correlated with the inhibition of noradrenaline uptake and both were correlated with plasma concentration of unchanged drug at all times and doses tested. Thus, milnacipran, when given orally to man, circulates in a biologically active form with similar potency for the inhibition of 5HT and noradrenaline uptake.