Biomedical subjects

J M Cardot

Publications and source records attributed to J M Cardot.

17 recordsLinked to original sources

PubMed1998

The effect of age on the pharmacokinetics of valsartan.

Twelve young (mean age 23 years, range 18-28) and 12 elderly (mean age 76 years, range 65-89) volunteers were given a single oral dose of 80 mg valsartan after an overnight fast. Each group consisted of six male and six female subjects. Mean systemic exposure to valsartan was higher in the elderly when compared with the young (AUC(0-24 h), 52% increase and AUC(0-infinity), 70% increase). Variability, as shown by the coefficient of variation (CV), was larger for the elderly subjects and ANOVA of the log transformed AUC showed a significant difference between the two groups. This difference was largely brought about by five elderly subjects (one male, four females), whose AUC was about 2-fold higher than the rest of the group. For the remaining elderly subjects, plasma valsartan AUC was similar to that observed for the young volunteers. This higher systemic exposure in five of the elderly subjects is not thought to be of clinical relevance when data from the patient population are considered. Other covariates--such as body weight, comedication, creatinine clearance, valsartan kinetics (absorption rate, distribution, and elimination)--did not explain the higher AUC in this subset of the elderly group. Data from the present study were compared with population kinetic data obtained from larger clinical trials including hypertensive patients in all age groups. Using this population approach, there was no difference in the pharmacokinetics of valsartan between male and female patients. Also, a relationship between plasma clearance of valsartan and age was established. The median age of patients in the hypertensive pool was 55 years. For an average 70-year-old patient, plasma clearance of valsartan is predicted to fall by 22% compared with an average 55-year-old. For the population this difference is not sufficient to warrant initial dose adjustment based on age per se. The covariate age, does not completely explain the variability in the pharmacokinetics of valsartan within the general population. The treatment was well tolerated.

Administration, Oral↗

PubMed1998

The influence of food on the disposition of the antiepileptic rufinamide in healthy volunteers.

The effect of food on the pharmacokinetics of the antiepileptic rufinamide was investigated in healthy volunteers. Twelve subjects were treated with single pre-oral doses of 600 mg of rufinamide after overnight fasting or a fat and protein rich breakfast. Mean (+/- S.D.) areas under the plasma concentration-time curves (AUCs) of the unchanged compound were 57.2 (16) micrograms mL-1 h when given to the fasted volunteers and 81.7 (22.2) micrograms mL-1 h (p = 0.0001) when given after the breakfast. The average AUC was increased by 44% when rufinamide was given with food and the maximum concentration (Cmax) by about 100%. The time at which Cmax was reached (tmax) was shorter (8 h in fasted conditions and 6 h in fed after breakfast); the terminal half-life was not influenced by concomitant intake of food.

Administration, Oral↗

PubMed1997

Absolute bioavailability of letrozole in healthy postmenopausal women.

Letrozole is a new non-steroidal inhibitor of the aromatase enzyme system. It is currently under development for the treatment of postmenopausal women with advanced breast cancer. Absolute bioavailability of letrozole when given orally as one 2.5 mg film-coated tablet in comparison to the same dose given intravenously as a bolus injection was studied in 12 healthy postmenopausal women. Letrozole absolute systemic bioavailability after p.o. administration was 99.9 +/- 16.3%. Elimination of letrozole was slow. Total-body clearance of letrozole from plasma after i.v. administration was low (2.21 L h-1). The calculated distribution volume at steady state (1.87 L kg-1) suggests a rather high tissue distribution. Biotransformation of letrozole is the main elimination mechanism with the glucuronide conjugate of the secondary alcohol metabolite being the predominant species found in urine. The two study treatments were tolerated equally well.

Administration, Oral↗

PubMed1997

Influence of food on glycemia, insulin, C-peptide and glucagon levels in diabetic patients treated with antidiabetic metformin at steady-state.

Seventeen diabetic patients (5 males and 12 females) treated with long-term metformin therapy received their morning dose after an overnight fast or after one of four types of breakfast: low protein, low fat, low carbohydrate or standard. Mean (+/- SD) and median areas under the serum concentration curves (AUC), maximum concentrations (Cmax) and time to reach the maximum concentrations (tmax) were calculated for the major biological parameters (glycemia, C-peptide, insulin and glucagon levels). None of the diets were bioequivalent to the fasting condition and only the low carbohydrate diet gave comparable results. A strong relationship was found between the carbohydrate intake (in g) and the AUC of the various markers except glucagon.

Adult↗

PubMed1995

Comparison of plasma and saliva concentrations of the active monohydroxy metabolite of oxcarbazepine in patients at steady state.

A study was performed in ten patients, stabilized with oxcarbazepine monotherapy (450-750 mg bid) for two weeks minimum, to investigate the possibility of using saliva to monitor the oxcarbazepine therapy. Thirteen paired blood and saliva samples were taken over 24 h. The saliva samples were obtained after stimulation. The analysis performed on the data suggests a dose dependence for the relationship between plasma and saliva concentrations of the main active metabolite, 10, 11-dihydro-10-hydroxycarbamazepine (MHD), and the importance of the type of stimulation for the saliva's production. Therefore it would be preferable to use plasma concentrations to monitor oxcarbazepine therapy, if necessary.

Adult↗

PubMed1994

The influence of food on the disposition of the antiepileptic oxcarbazepine and its major metabolites in healthy volunteers.

The effect of food on the pharmacokinetics of the antiepileptic oxcarbazepine (OXC) was investigated in healthy volunteers. Six healthy male volunteers were treated with single peroral doses of 600 mg of oxcarbazepine (Trileptal) after overnight fasting or a fat- and protein-rich breakfast. Mean (+/- SD) areas under the plasma concentration-time curves (AUC) of the major component in plasma, the active monohydroxy metabolite (MHD), which is responsible for the therapeutic effect in man, were 672 (25) mumol L-1 h when given to the fasted volunteers and 780 (31) mumol L-1 h (p = 0.042) when given after a substantial breakfast. Mean (+/- SD) maximum concentrations (Cmax) were 25.5 (4.8) mumol L-1 when given to the fasted volunteers and 31.4 (5.3) mumol L-1 (p = 0.025) when given after breakfast. Thus, the average AUC was increased by 16% and Cmax by 23% when oxcarbazepine was given with food. The times at which Cmax was reached (tmax) as well as the terminal half-lives were not influenced by concomitant intake of food. The tolerability was the same whether oxcarbazepine was given before or after food in healthy volunteers. The slight effect of food on the kinetics of oxcarbazepine should be of little therapeutic consequence.

Administration, Oral↗

PubMed1994

Pharmacokinetics of rec-hirudin in healthy volunteers after intravenous administration.

The pharmacokinetics of recombinant hirudin (rec-hirudin, Ciba-Geigy, CGP 39,393) in healthy volunteers after iv administration was investigated on the basis of the data from five different studies. A total of 77 plasma profiles following a single iv bolus dose of either 0.1, 0.3, 0.5, or 1 mg/kg of rec-hirudin was used for the evaluation. Plasma concentrations and especially AUC were proportional to the dose. Kinetics of rec-hirudin after a bolus iv injection were best described by a three-compartment open model. Mean apparent terminal half-life was 2.8 hr and the total clearance 0.138 L/hr per kg.

Adult↗

PubMed1993

Influence of food on the disposition of the monoamine oxidase-A inhibitor brofaromine in healthy volunteers.

The effect of food on the bioavailability of brofaromine hydrochloride was investigated in a randomized cross-over study. Eight healthy male volunteers were given single peroral doses of 75 mg brofaromine hydrochloride after overnight fasting or a fat- and protein-rich breakfast. Mean (+/- SD) areas under the plasma concentration-time curves (AUC) were 9.66 (2.35) mumol l-1 h when given to the fasted volunteers and 11.82 (3.78) mumol l-1 h (p = 0.0413) when given after a substantial breakfast. Mean (+/- SD) maximum plasma concentrations (Cmax) were 0.71 (0.13) mumol l-1 when given to the fasted volunteers and 0.85 (0.22) mumol l-1 (p > 0.05) when given after breakfast. Thus, both the average AUC and Cmax were increased by approximately 20 per cent when brofaromine hydrochloride was given with food. The times when Cmax was reached (tmax) as well as the elimination half-lives were not influenced by concomitant intake of food. The tolerability was the same whether brofaromine was given before or after food in healthy volunteers. The slight effect of food on the bioavailability of brofaromine should be of little therapeutic consequence because of the observed wide inter-subject variability of the plasma levels.

Adult↗

PubMed1993

Comparative pharmacokinetics of free muramyl tripeptide phosphatidyl ethanolamine (MTP-PE) and liposomal MTP-PE.

The comparative pharmacokinetics of free MTP-PE (muramyl tripeptide phosphatidyl ethanolamine) and MTP-PE entrapped in negatively charged multilamellar liposomes (liposomal MPT-PE) was evaluated in rats at a bolus intravenous (i.v.) dose of 0.2 mg/kg and in dogs at a bolus i.v. dose of 0.1 mg/kg. Additional studies were performed with the free form in rats (1.4 mg/kg, bolus i.v.) and dogs (1 mg/kg, bolus i.v.) and with the liposomal form in dogs (0.5 mg/kg, bolus i.v.). Plasma samples were obtained at various times up to 48 h postinjection and assayed for the drug by a chemiluminescence immunoassay. The pharmacokinetic data regarding liposomal MTP-PE describe the distribution of free drug released from liposomes and total drug concentrations. The present studies demonstrate that the distribution characteristics of MTP-PE changed dramatically depending on the dosage form. The elimination kinetics of free MTP-PE from blood is substantially slower than that of the liposomal drug. For liposomal MTP-PE, free drug levels in plasma are very low compared with free MTP-PE. In rats at a dose of 0.2 mg/kg, 96% of MTP-PE contained in liposomes is removed from the plasma compartment 10 min after injection, and in dogs at a dose of 0.1 mg/kg, 100% of MTP-PE contained in liposomes is removed in the same time period. This rapid phase of liposome clearance is followed by a slower rate of clearance for the remainder of the liposomes in rats at a dose of 0.2 mg/kg and in dogs at a dose of 0.5 mg/kg.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1987

The influence of food on the bioavailability of a slow release theophylline preparation.

Food-induced changes in the absorption of Theostat 300, a controlled release formulation of theophylline, have been studied in healthy volunteers. This open, randomised, 3-way, single-dose study involved 12 volunteers who received the drug either while fasting, or with a standardised low-fat (10g), or high-fat (60g) breakfast. Each subject was studied over a 3-week period, with 3 separate days of oral treatment and a 7-day washout period between treatments. The results showed no differences in AUC0-24 and tmax values between the 3 kinds of diet. The only differences observed concerned absorption. Food intake increased Cmax values by 20%. The steady-state peak concentration obtained by means of simulated plasma levels was not influenced by food intake. This slight food-drug interaction of Theostat 300 seemed to be of no clinical significance.

Adult↗

PubMedDate not supplied

Inter- and intra-subject variability of metoprolol kinetics after intravenous administration.

The pharmacokinetics of metoprolol were assessed from the data of 3 experiments in which intravenous deuterated metoprolol was given concomitantly with various oral metoprolol formulations to healthy volunteers. The plasma levels after intravenous administration were well described by a biexponential equation. However, a deviation from a pure biphasic decline was observed over a short period of time, immediately after the rapid elimination phase. The inter- and intra-subject variability of the parameters describing the two-compartment model was large. The intra-subject variability of the terminal half-life and the plasma clearance was lower than their inter-subject variability. The plasma clearance was linearly related to 1/t1/2. Contrarily to the other parameters of the model, t1/2 appeared to be a characteristic of the subject.

Adult↗

PubMedDate not supplied

Stable isotope methodology for studying the performance of metoprolol Oros tablets in comparison to conventional and slow release formulations.

Metoprolol Oros tablets were designed to deliver their drug content as a constant rate over a period of time longer than that currently recorded with slow-release dosage forms. The bioavailability of 7/95, 14/190 and 21/285 Oros tablets was compared to that of either 100 mg conventional or 200 mg slow-release Lopresor tablets in 3 two-period change over experiments. In each experiment, 6 healthy volunteers received intravenous deuterated metoprolol concomitantly with one of the Oros systems or with one of the other two formulations. The Oros tablets gave rise to lower and steady plasma levels of metoprolol over 24 h than the other formulations. Their mean absorption time was around 3 times longer than that of the slow-release tablets. The amount of the drug absorbed unchanged was linearly related to the dose. The influence of the gastrointestinal transit time on the performance of Oros tablet was limited. These studies demonstrated the value of the stable isotope methodology in bioavailability assessment for drugs presenting a high inter-subject variability in their plasma clearance such as metoprolol.

Absorption↗

PubMedDate not supplied

LIMS: from theory to practice.

This paper gives a definition and some basic knowledge about Laboratory Information Management Systems (LIMS) as well as their impact on the organisation, the laboratory and the co-workers. The major advantages and disadvantages of LIMS are pointed out. Two practical experiences are described. The first is related to an in house development of a PC based system which has to integrate a Vax VMS system (Multichrom) and PC based analytical and analysis softwares. The second experience is dealing with the selection and implementation of a commercial package in a pharmacokinetic laboratory. In both cases the human and time aspects were important.

Clinical Laboratory Information Systems↗

PubMedDate not supplied

Pharmacokinetics of cefotaxime and its desacetyl metabolite in plasma and in cerebrospinal fluid.

The aim of the study was to investigate the pharmacokinetic modelling of Cefotaxime (CTX) and its main metabolite Desacetyl Cefotaxime (DCTX) which has a less antibacterial activity than the CTX. After intravenous administration of 1g of CTX to 26 patients, the plasma concentrations determined by HPLC showed that the pharmacokinetics of CTX and transformation to DCTX can be described with an open five-compartment model. The implications of this are discussed from the clinical point of view.

Adolescent↗

PubMedDate not supplied

Bioequivalence assessment: a pharmaceutical industry perspective.

Various aspects of bioequivalence are investigated in this paper. Some aspects dealing with bioequivalence studies conducted either during the development of the drug or after its marketing will be presented and discussed: Bioequivalence of highly variable drugs with the associated problem of widening the acceptance range or alternative solutions. Bioequivalence for the final market image. Bioequivalence for investigating the food effect. Bioequivalence in special population such as children, non Caucasian population. Bioequivalence based on in vitro data or literature. New approaches in bioequivalence interpretation. Bioequivalence and analytical methods which are not sensitive or specific enough.

Biological Availability↗

PubMedDate not supplied

Bioinversion of ibuprofen enantiomers after administration in dogs: estimation of a novel index.

This study compares the pharmacokinetics and bioinversion of two chemical forms of ibuprofen administered intravenously or orally. Dogs were given the free acid form of the S(+) isomer p.o. or i.v., or the racemate, as the free acid or sodium salt, p.o., in a cross-over design. The main kinetic parameters were calculated and formation and bioinversion curves plotted. The values of Cmax, Tmax and AUC were higher for the S(+) isomer. The percentage bioinversion averaged between 35-70% according to the form. This study proposes a new index for the calculation of bioinversion, independently of any i.v. administration, and confirms its self-limiting nature.

Animals↗

PubMedDate not supplied

In vitro/in vivo correlations: scientific implications and standardisation.

In vitro/in vivo correlations and the parameters that should be correlated have now been well defined in the USP and FDA working group proposals. Among the three levels of correlation defined, Level A is the most interesting one. In this paper, the Level A correlation is studied from a mathematical and a biopharmaceutical point of view. The conditions that must be met before attempting to establish correlations and the place of in vitro/in vivo correlation in modified release drug dosage form development are discussed. To establish in vitro/in vivo correlations requires a strict development methodology in order to obtain them in the most favourable conditions. In vitro/in vivo correlations should be sought as early as possible during the dosage form development (a priori correlations). If the formulation has been undertaken first and correlations sought on the finished product from subsequent in vitro tests, the predictive power of these correlations (a posteriori correlations) is thus limited and they require additional validation.

Animals↗