Biomedical subjects

C Puozzo

Publications and source records attributed to C Puozzo.

15 recordsLinked to original sources

PubMed2005

Intravenous busulfan in adults prior to haematopoietic stem cell transplantation: a population pharmacokinetic study.

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.

Adult↗

PubMed2004

I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients.

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 children < or =4 years old and 0.8 mg/kg for patients >4 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.

Adolescent↗

PubMed2003

Phase I and pharmacokinetic study of the new vinca alkaloid vinflunine administered as a 10-min infusion every 3 weeks in patients with advanced solid tumours.

BACKGROUND: Vinflunine is a novel vinca alkaloid obtained by semi-synthesis using super-acidic chemistry to selectively introduce two fluorine atoms at the 20' position of vinorelbine. In human tumour xenografts, vinflunine showed definite antitumour activity in seven out of 11 tumours tested compared with three out of 11 for vinorelbine. PATIENTS AND METHODS: In this phase I study, vinflunine was administered to 31 patients with advanced malignancies as a 10-min i.v. infusion every 3 weeks according to an escalating schedule of doses between 30 and 400 mg/m(2). RESULTS: Pharmacokinetic parameters and toxicities were assessed and, at 400 mg/m(2), three out of five patients experienced dose-limiting toxicity. At the maximum tolerated dose (MTD), i.e. 400 mg/m(2), the toxicity profile of vinflunine consisted mainly of mucositis, constipation and neutropenia of short duration. Vinflunine area under the curve increased as a proportion of the administered dose whereas no saturation of elimination was observed. CONCLUSION: The MTD of vinflunine was achieved at 400 mg/m(2) every 3 weeks. According to protocol rules, the recommended dose was established at 350 mg/m(2). A preliminary assessment of first patients included in early phase II trials led to reduction of the recommended dose to 320 mg/m(2) every 3 weeks for further development of vinflunine. Three partial responses (two in breast carcinoma, one in renal cell carcinoma) suggest that activity is likely to be seen in less heavily pretreated patient populations.

Adult↗

PubMed2001

New sensitive liquid chromatography method coupled with tandem mass spectrometric detection for the clinical analysis of vinorelbine and its metabolites in blood, plasma, urine and faeces.

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.

Antineoplastic Agents, Phytogenic↗

PubMed2001

Oral vinorelbine pharmacokinetics and absolute bioavailability study in patients with solid tumors.

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 fasted and were randomised to receive vinorelbine on day 1, either as a 20 minute intravenous (i.v.) infusion of 25 mg/m2 or as softgel capsules at a dose of 80 mg/m2. 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/m2 (Tmax 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/m2 oral and 30 mg/m2 i.v., and between 60 mg/m2 oral and 25 mg/m2 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 AUClast 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/m2 oral vinorelbine than by 25 mg/m2 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.

Administration, Oral↗

PubMed2001

Information tools for exploratory data analysis in population pharmacokinetics.

For a group of individuals, population pharmacokinetic studies describe the interindividual variability through a statistical distribution. These studies conducted during the drug development serve as a useful marker of the safety of the drug, provide information that might be decisive for future experiments and, in a clinical context, help establish guidelines for optimal use in each patient. As complementary tools to the existing statistical and graphical techniques for population pharmacokinetic data analysis, indexes derived from information theory were used to select the most appropriate modelfor the statistical distribution, to detect atypical individuals, and to screen influential covariates. The rationale for using these indexes is shown using simulated and real data.

Humans↗

PubMed1998

Validated method for the determination of idazoxan in human plasma by liquid chromatography with tandem mass spectrometric detection.

A liquid chromatography-tandem mass spectrometry method for the determination of idazoxan in human (heparin) plasma is presented, which was developed and validated using 500 microl of sample. Sample preparation consisted of the addition of fluoroidazoxan as the internal standard, extraction at alkaline conditions into tert.-butyl methyl ether, followed by centrifugation, evaporation of the solvent and reconstitution in methanol. After a short chromatographic run, detection took place by ionspray tandem mass spectrometry in positive ion mode. Validation results on linearity, specificity, accuracy, precision and stability, as well as application of the method to samples from a clinical trial, are shown. The validated calibration range is from 0.300 to 100 ng/ml, with accuracy (bias) and precision (coefficient of variation) being below 15% at all levels. A sample throughput of, typically, 150 per day can be achieved.

Chromatography, Liquid↗

PubMed1996

Pharmacokinetics of milnacipran in comparison with other antidepressants.

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.

Adrenergic Uptake Inhibitors↗

PubMed1993

Acute electrophysiological effects of intravenous milnacipran, a new antidepressant agent.

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 alterations 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 < 0.005), and decreases in the functional refractory period of the atrium (-3%, P < 0.05), the atrioventricular node (-9%, P < 0.005) and the effective refractory period of the right ventricle (-10.8%, P < 0.05) at 50 min. The sinus node function was improved in nine patients but depressed in one patient with previous slight baseline sinus node alterations. Milnacipran being devoid of both anticholinergic and monoamine oxidase inhibition activities, these alterations could be related to inhibition of noradrenaline uptake leading to an increase of adrenergic activities. No other ECG or electrophysiological parameters were significantly altered. Five of the 10 patients reported transient nausea, four of them for the highest dosage (0.8 mg/kg) and at the moment of peak of milnacipran plasma level. In conclusion, electrophysiological effects of intravenous milnacipran are negligible. These findings differ from those, well described in the literature, for imipramine-like antidepressant agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1992

Effects of prolonged administration of milnacipran, a new antidepressant, on receptors and monoamine uptake in the brain of the rat.

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 beta-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 beta-adrenoceptors. In addition, there were no alterations of alpha 1- or alpha 2-adrenoceptors, 5-HT1, 5-HT2 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 beta-adrenoceptors or the other receptors studied, suggesting that, at least for this antidepressant, these modifications are not essential for clinical activity.

Animals↗

PubMed1989

Monoamine uptake inhibition by plasma from healthy volunteers after single oral doses of the antidepressant milnacipran.

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.

Adult↗

PubMed1989

Differences in the metabolism of epicainide in rats and man.

1. Epicainide is a new potent antiarrhythmic agent, metabolized differently in rats and man. 2. In rats, the aromatic part of the molecule (the two phenyl rings linked to the quaternary carbon atom) undergoes metabolic attack by the mono-oxygenases. The hydroxy and methoxy-hydroxy metabolites are predominant and are excreted in urine and bile both as free and conjugated forms. 3. In contrast, the aromatic moiety of epicainide remains unchanged in man. It is the ethylpyrrolidine ring which is mainly attacked, resulting in the expected N-deethylation, subsequent oxidation of the pyrrolidine moiety, and reduction or hydrolysis of the amide function. 4. A preliminary kinetic analysis of epicainide in man reveals a linear open 2-compartment model. The radioactivity recoveries confirm the absence of any accumulation of the drug in the organism.

Adult↗

PubMedDate not supplied

Which bioequivalence study for a racemic drug? Application to milnacipran.

Milnacipran, a new non tricyclic antidepressant drug, is a racemic mixture (F2207) composed of two enantiomers: F2695 and F2696, both demonstrated to be active. A randomized open label, single-dose latin square study was undertaken in 24 healthy volunteers to compare, based on racemate data, the relative bioavailability of two new formulations to that of a reference formulation. Later on, as suggested by actual regulatory trend, analysis was carried out on enantiomer data, although in a supportive way. Bioequivalence was assessed on calculation of 90% confidence intervals for log-transformed Cmax and AUC(0-infinity) and on Wilcoxon test for Tmax with a 5% level of significance. Based on racemate data, both test formulations were demonstrated to be equivalent to the reference capsule in terms of Cmax and AUC-(0-infinity). Differences in Tmax reached statistical significance, although their mean magnitude was small, and probably not relevant when related to antidepressant long-term therapy. When considering the test capsule - reference capsule comparison, the equivalence demonstrated for the racemate reflect that of each enantiomer. On the contrary, equivalence between the test tablet and the reference capsule demonstrated for the racemate, is not supported by both enantiomers as Cmax of F2696 fails to reach bioequivalence criteria, making more uncertain the conclusion of bioequivalence. From this experience, it seems than when equivalence is demonstrated close to the limits for the racemate, it is difficult, especially for a low variability drug such as milnacipran, to comply with equivalence criteria for both enantiomers.

Adult↗

PubMedDate not supplied

Pharmacokinetics of milnacipran in liver impairment.

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.

Administration, Oral↗

PubMedDate not supplied

Pharmacokinetics of milnacipran in renal impairment.

The pharmacokinetics of a single 50 mg dose of milnacipran, a new non tricyclic antidepressant drug, were compared in 8 chronic renal failure subjects (Clc(reat) between 9 to 84.5 ml.min(-1)) and in 6 healthy volunteers. Concentrations of unchanged (F2207 racemate and F2695 and F2696, enantiomers) and glucuroconjugated drug (main metabolite) were measured using HPLC and GC-MS. As for drugs mainly eliminated via renal route, the pharmacokinetics of milnacipran were markedly affected by impaired renal function with the elimination half-life of severely impaired subject being approximately three times that of the control group. Milnacipran apparent total clearance and renal clearance were positively correlated with glomerular filtration rate, while non-renal clearance and apparent volume of distribution were unaffected by renal impairment. Plasma concentrations of the glucuroconjugate were gradually increased in plasma, while its total urine excretion remained unchanged. As for the racemate, pharmacokinetics of each enantiomer were modified by renal failure, although, as predictable from its higher renal clearance value, it was more marked for F2696 than for F2695. Considering that modifications were shown to be proportional to the degree of renal impairment and that milnacipran presents low variability, the necessary dose adjustment is therefore easy to predict.

Adult↗