Kinetics of five benzodiazepine hypnotics in healthy subjects.

Kinetics of five benzodiazepine hypnotics (15 mg flurazepam, 1 mg flunitrazepam, 5 mg nitrazepam, 10 mg temazepam, and 0.5 mg triazolam) were compared in the same group of 12 healthy subjects. Plasma concentrations of parent drugs were determined by capillary gas chromatography with electron-capture detection. For flurazepam, the N-desalkyl metabolite (DAF) was measured. Flunitrazepam, nitrazepam, temazepam, and triazolam were rapidly absorbed, although there was considerable variability; mean peak times (ranges) were: 1.3 (0.3 to 3) hr, 1.8 (0.7 to 6) hr, 1.2 (0.3 to 4) hr, and 1.1 (0.7 to 2) hr. Plasma concentrations of DAF increased rather slowly and reached their maximum between 3 and 48 hr after flurazepam. There were considerable differences in elimination t1/2s, with means of 35 (15 to 66) hr for flunitrazepam, 28 (22 to 33) hr for nitrazepam, 12 (8 to 22) hr for temazepam, 2.4 (1.4 to 3.9) hr for triazolam, and 84 (40 to 114) hr for DAF. Sex differences in elimination t1/2 were only observed for DAF: 99 hr in women and 69 hr in men. Our results show that there are considerable differences in the kinetics of the diazepines.

Pharmacokinetic-pharmacodynamic modeling of the effects of ivabradine, a direct sinus node inhibitor, on heart rate in healthy volunteers.

OBJECTIVE: Ivabradine (S-16257) is a new bradycardic agent with a direct effect on the sinus node. Its N-dealkylated metabolite, S-18982, has shown a bradycardic activity in animals. The aim of this trial was to study the correlation between drug bradycardic activity and plasma levels of the parent compound and its metabolite in healthy volunteers. METHODS: Eighteen healthy volunteers participated in three successive study periods: an oral double-blind period with two parallel groups of doses (10 or 20 mg, single and repeated); a 10 mg intravenous bolus open period; and a final control period. The effects of ivabradine on heart rate were studied at rest and during bicycle exercise tests (at 85% of maximum workload) during 24-hour postdosing, and ivabradine and S-18982 plasma levels were determined simultaneously. RESULTS: The maximal reductions of exercise heart rate were 11% +/- 4% (10 mg) and 18% +/- 6% (20 mg) after single oral doses (p < 0.05) and 18% +/- 4% (10 mg) and 27% +/- 6% (20 mg) after repeated doses (p < 0.01). Maximum heart rate reduction after the intravenous bolus was 19% +/- 4%. After oral administrations an indirect relationship between the bradycardic effect and the plasma concentrations of the two compounds was found. A pharmacokinetic/pharmacodynamic population analysis done with the NONMEM computer program showed that S-18982 contributes in part to the overall activity of ivabradine: modeling suggested that the metabolite is responsible for the initial bradycardic effect, whereas the parent compound is responsible for the duration of action. CONCLUSION: This study shows that ivabradine exerts a dose-dependent bradycardic effect and that its N-dealkylated metabolite contributes to this bradycardic effect.

Pharmacokinetic-pharmacodynamic modelling in the early development phase of anti-psychotics: a comparison of the effects of clozapine, S 16924 and S 18327 in the EEG model in rats.

1. The use of pharmacokinetic/pharmacodynamic (PK/PD) analysis in early compound development was investigated in the rat for two developmental anti-psychotic compounds with clozapine as a positive control. 2. Three plasma samples were collected from each of eight animals according to a pre-defined sampling matrix allowing a total of 12 time points for PK analysis. Quantitative electroencephalography (QEEG), particularly the theta and beta frequencies, was used as a measurement of pharmacological effect. 3. PK/KD modelling of the sparse PK data available relative to a rich set of PD data was achieved using a population approach in NONMEM (IV). Individual PK parameter estimates were incorporated into a PK/PD model. 4. Qualitative EEG changes in rat and human were similar for clozapine, but different for the two developmental compounds, suggesting that changes in these PD parameters may not be specifically related to the anti-psychotic activity. 5. Although no definitive data are available concerning the signal specificity of EEG frequency bands with respect to dopaminergic or serotonergic receptor activity, qualitative and quantitative differences seen in EEG parameters are likely to result from the multiple receptor occupancy for these compounds. 6. The results confirm the value of population PK/PD modelling in conjunction with sparse sampling to enable determination of concentration effect relationships in the pre-clinical development programme of CNS-active drugs.

Melting process and interface instability of highly magnetized solid 3He: role of the magnetization gradient

We elucidate the melting process of highly magnetized solid 3He by observing the magnetization profile and the liquid-solid interface simultaneously. Clear enhancements of magnetization and magnetization gradients at the interface of both the solid and the liquid were observed during melting. These measurements provide a mesoscopic confirmation of the melting scenario of Castaing and Nozieres, and explain the long delay before the instability sets in: The magnetization gradient in the liquid leads to an initial suppression of the melting instability, in accordance with our extension of the stability analysis of Puech et al. This resolves the discrepancy between theory and experiment.

Application of population pharmacokinetics to the phase II development of an anti-Alzheimer's disease compound, S12024.

Steady-state concentrations of S12024, a novel compound for treatment of Alzheimer's disease, were studied to determine the pharmacokinetic parameters of S12024 in Phase IIa patients and to assess the effect of patient characteristics on those pharmacokinetics. A prospective sparse sampling strategy was used to obtain oral repeated data (n = 285) from 89 patients, which were analyzed using a one-compartment model and the NONMEM computer program. The model suggested that apparent clearance of S12024 was influenced by the study and by patient age. In the Spanish study, apparent clearance was increased by 68% and 26% for doses of 100 mg and 300 mg, respectively, and patient age decreased oral clearance by approximately 10% per decade in the patient age range (50 to 90 years). Data from only a few patients in the Spanish study were probably responsible for the observed study influence on apparent clearance of S12024, and no measured covariates could explain this effect. The model provided an excellent characterization of the observed data and it predicted correctly the plasma concentrations from an earlier Phase I trial and a subsequent Phase IIb study. The present model, built from Phase IIa data, provides a basis for examining the influence of patient covariates and the magnitude of their effects on the pharmacokinetics of S12024. The study effect is probably an artefact that will disappear by further expanding of the population model in the future.

Population pharmacokinetic-pharmacodynamic modelling of S 15535, a 5-HT(1A) receptor agonist, using a behavioural model in rats.

The pharmacokinetic-pharmacodynamic relationship of S 15535 (1-(benzodioxan-5-yl) 4-(indan-2-yl)piperazine) and its active 5-hydroxy metabolite S 32784 (1-(benzodioxan-5-yl) 4-(5-hydroxyindan-2-yl)piperazine), and buspirone as a reference, were studied in male Wistar rats using a behavioural model of anxiety by determining the reduction in the number of fear-induced ultrasonic vocalisations. S 15535 and buspirone were administered p.o. and i.v. S 32784, present in man but not in rat, was administered i.v. The pharmacokinetics and pharmacokinetic-pharmacodynamic relationships were described using non-linear mixed effects modelling. The no-drug effect was constant and all compounds were active in the model, reducing ultrasonic vocalisations immediately after administration. The sigmoid E(max) model was used to describe the pharmacokinetic-pharmacodynamic relationships, with E(max) values of a 90% decrease in baseline ultrasonic vocalisations. Corrected for plasma protein binding, all compounds showed similar potency. The study shows that ultrasonic vocalisations can be considered a suitable endpoint for the anxiolytic effect when used in conjunction with non-linear mixed effects modelling to overcome the limited sampling and effect measurements.

Pharmacokinetics of benzodiazepines: metabolic pathways and plasma level profiles.

Large differences exist among the various benzodiazepines with regard to their pharmacokinetic properties and metabolism in man. Some are eliminated from the body at a relatively slow rate, e.g. desmethyldiazepam, and others are metabolized rapidly, e.g. midazolam, triazolam. Several benzodiazepines have major active metabolites that are slowly eliminated, e.g. medazepam, halazepam , quazepam and, consequently, should be considered as potentially long-acting. Such differences may be very important clinically because pharmacokinetic data will help to optimize drug therapy with respect to the choice of the proper drug and drug preparation, as well as with the choice of a proper dose and dosage regimen. The therapeutic objectives of drug therapy differ quite considerably for the various clinical indications of benzodiazepines. In anti-anxiety and anti-epileptic therapy, prolonged or continuous treatment is pursued, so that compounds with relatively long or intermediate elimination half-lives of parent drug or active metabolites are of advantage. In hypnotic treatment, on the other hand, the duration of drug action should be restricted to the duration of the night, hence a compound with a short elimination half-life may be preferred. An overview is given of the pharmacokinetics of the major benzodiazepines currently available and of some interesting new ones that are still in the development stage.

Pharmacokinetics of sustained and immediate release formulations of indapamide after single and repeated oral administration in healthy volunteers.

The pharmacokinetics of a 2.5 mg immediate release (IR) formulation of indapamide was compared to a 1.5 mg sustained release (SR) formulation of indapamide after single and repeated oral administration dose using double blind randomised cross-over studies. In the first study, 12 subjects received a single dose of each treatment: IR fasted, SR fasted or with food. In the second study one tablet of either formulation was administered daily for one week at breakfast. In each study, blood samples were collected pre dose (Cmin) and up to 120 h after the last dose. Urine was collected over the dosing interval (24 h). Following a single oral administration the SR formulation had a lower dose-normalised Cmax compared to the IR formulation (17.6 +/- 6.3 vs. 39.3 +/- 11.0 ng x mL(-1), respectively), a much longer t(max) (12.3 +/- 0.4 vs. 0.8 +/- 0.3 h) and a greater t75 (15.3 +/- 6.1 vs. 1.8 +/- 1.4 h) but there were no differences in dose-normalised AUC (559 +/- 125 and 564 +/- 146 ng x h x mL(-1)) nor in t(1/2z) values (14.8 +/- 2.8 vs. 18.4 +/- 13.4 h). The SR formulation clearly demonstrated sustained release characteristics as compared to the IR formulation. Food co-administration had no effect on dose-normalised AUC for the SR formulation. After repeated administration, steady-state was achieved by day 5. The absorption rate of the SR formulation was lower and the 24 h peak-to-trough fluctuation was 4-fold lower compared to the IR formulation. After dose correction there wasno change in AUC, (726 +/- 207 and 690 +/- 183 ng x mL(-1) x h for SR and IR, respectively). The elimination parameters (t(1,2z), Ae(tau), and CLr) remained unchanged. The SR formulation showed sustained release of indapamide with a reduction in peak concentration, while steady-state level was not affected by formulations. The two formulations have the same bioavailability.

Use of nonlinear mixed effect modeling for the meta-analysis of preclinical pharmacokinetic data: application to S 20342 in the rat.

The standard two-stage analysis of separate preclinical pharmacokinetic (PK) and toxicokinetic (TK) studies may lead to good information on the bioavailability in the rat at a low (pharmacologic) dose but only an idea on the dose/exposure relationship, on gender, and on time effect. In view of these drawbacks, we decided therefore to explore the usefulness of the implementation of a meta-analysis in preclinical studies in a given species (the rat in this case) taking as an example S 20342, an investigational new drug with potential antipsychotic properties. A nonlinear mixed-effect PK model was built from all intravenous (IV) and oral (PO) data collected until the completion of the 4-week toxicity study. The database included data from 201 Wistar rats (161 males and 40 females). Forty animals received the drug IV and 161 PO. The treatment duration ranged from 1 day to 4 weeks. IV doses were 3, 5, and 20 mg/kg, and 11 different oral doses were tested in the range of 5 to 200 mg/kg. Three different salts were administered PO: hydrochloride, sulfate, and mesylate. The modeling was performed with NONMEM IV. The best pharmacokinetic model was a two-compartment model with simultaneous first-order and zero-order absorption. The combination of these two input functions allowed the model to fit the peak plasma concentrations observed in the first hour (first order), especially after oral administration of low doses, and to take into account the prolonged absorption phase when the dose increased (zero order). A significant gender effect was found on CL. In addition, significant positive correlations were found between weight and CL, weight and Vc, and dose and the dose fraction after a zero-order absorption. No covariate significantly influenced the other parameters. In conclusion, the meta-analysis of preclinical data allowed for an objective assessment of statistically significant effects throughout the model-building process, leading to a better knowledge (and thus a better understanding) of preclinical PK in the rat. Moreover, the model obtained could be used to interpret further preclinical specific studies involving a sparse sampling design (e.g., further TK studies and PK/PD studies). Although this meta-analysis is more complicated than the noncompartmental approach and requires a case-by-case effort, it could be very useful to integrate this approach in the preclinical development process.

Prediction of interindividual variation in drug plasma levels in vivo from individual enzyme kinetic data and physiologically based pharmacokinetic modeling.

A strategy is presented to predict interindividual variation in drug plasma levels in vivo by the use of physiologically based pharmacokinetic modeling and human in vitro metabolic parameters, obtained through the combined use of microsomes containing single cytochrome P450 enzymes and a human liver microsome bank. The strategy, applied to the pharmaceutical compound (N-[2-(7-methoxy-1-naphtyl)-ethyl]acetamide), consists of the following steps: (1) estimation of enzyme kinetic parameters K(m) and V(max) for the key cytochrome P450 enzymes using microsomes containing individual P450 enzymes; (2) scaling-up of the V(max) values for each individual cytochrome P450 involved using the ratio between marker substrate activities obtained from the same microsomes containing single P450 enzymes and a human liver microsome bank; (3) incorporation into a physiologically based pharmacokinetic model. For validation, predicted blood plasma levels and pharmacokinetic parameters were compared to those found in human volunteers: both the absolute plasma levels as well as the range in plasma levels were well predicted. Therefore, the presented strategy appears to be promising with respect to the integration of interindividual differences in metabolism and prediction of the possible impact on plasma and tissue concentrations of drugs in humans.

A high performance normally closed solenoid-actuated cold valve.

An electromagnetically driven normally closed valve for liquid helium is presented, which is meant to regulate the input flow to a 1 K pot. An earlier design is modified to be normally closed (not actuated) and tuned for durability and reliability. A new feature is presented which prevents seat deformation at room temperature and provides comfort and durability for intensive use.

Complete bioavailability and lack of food-effect on pharmacokinetics of gliclazide 30 mg modified release in healthy volunteers.

A new modified release (MR) formulation containing 30 mg of gliclazide was developed to obtain a better predictable release of the active principle and to allow once-daily dosing regimen. An absolute bioavailability study was carried out to characterise the performance of the new formulation and the food-effect was also investigated in a separate study. Both studies were single dose, randomised, open label, two way cross over studies with a wash out period between doses. For the bioavailability study, each volunteer received 30 mg of gliclazide given either as a 1 h intravenous infusion or as a 30 mg MR tablet. For the food-effect study, the treatment was given either fasted or 10 min after the start of a standardised Melander breakfast. Blood samples were collected up to 72 h after administrations and plasma samples assayed for gliclazide concentrations using a reverse-phase HPLC method with UV detection. Mean absolute bioavailability of gliclazide was 97% and ranged between 79 and 110% showing complete absorption. A similar moderate to low variability was observed after IV and oral administration showing the MR formulation did not add to the overall variability which is solely due to the disposition parameters, in particular metabolism of gliclazide. No significant difference was observed in t(max), t(1/2z), C(max) and AUC of gliclazide after administration of the 30 mg MR tablet under fasted and fed conditions. In conclusion, after single oral administration of a 30 mg MR tablet, gliclazide was completely absorbed both under fasted and fed conditions. A consistent and optimal release of gliclazide from this formulation leads to a low to moderate overall variability of its pharmacokinetic parameters. Diamicron 30 mg MR can be given without regards to meals i.e. before, during or after breakfast.

Pharmacokinetics of temazepam compared with other benzodiazepine hypnotics--some clinical consequences.

When the various benzodiazepine hypnotics are studied, large differences are seen with regard to their pharmacokinetic properties and metabolism in man. Some are eliminated from the body at a relatively slow rate (e.g. nitrazepam), others are metabolized rather rapidly (temazepam, triazolam). Some benzodiazepine hypnotics have major active metabolites that are slowly eliminated (flurazepam, quazepam), while others have non-active metabolites (temazepam, lormetazepam). In hypnotic treatment, the duration of drug action should be restricted to the duration of the night, hence a compound with a relatively short elimination half-life may represent a more rational choice. An overview is given of the pharmacokinetics of the currently available benzodiazepine hypnotics with emphasis on temazepam and other hydroxylated benzodiazepines.

Assessment of drug exposure in rat dietary studies.

1. The objective of this study was to justify the evaluation of exposure of animals to chemical substances on the basis of only three blood samples taken during a 24-h period, but still with acceptable accuracy. 2. Fischer rats were fed a diet mixed with either paracetamol, 100 mg.kg-1 (short half-life compound), antipyrine, 100 mg.kg-1 (medium half-life compound), or phenylbutazone, 50 mg kg-1 (long half-life compound) for 3 weeks. It had been shown in a preliminary study that these compounds when administered at these dose levels did not influence feeding behaviour. At the end of 3 weeks, five rats were sampled every 3 h beginning and ending at 19.00 h (45 rats in total) and plasma concentrations were measured using h.p.l.c. 3. The area under the curve over 24 h (AUC24), calculated using all nine concentrations was considered to be the true AUC24. Subsequently, estimates of this parameter were made using different combinations of concentrations at three or even two selected time points. 4. For each compound, the highest concentration occurred at 07.00 h. It was shown that using the concentrations at 07.00, 10.00 and 16.00 h the estimate of the AUC24 was within 15% of the true value. 5. In comparison with a gavage study in the same rat (strain and age), bioavailability was lower in the diet study with relative bioavailabilities of 27, 22 and 61% for paracetamol, antipyrine and phenylbutazone, respectively. 6. In conclusion, drug exposure as expressed by AUC24 and Cmax can be accurately determined in rat studies using compound administration in the diet by measuring concentrations at three selected time points for compounds with elimination half-lives ranging from about 1 to 5 h.

Pharmacokinetics of benzodiazepines. Short-acting versus long-acting.

Among the various benzodiazepines large differences exist with regard to their pharmacokinetic properties and metabolism in man. Some are eliminated from the body at a relatively slow rate (e. g. diazepam), others are metabolized rather rapidly (e. g. oxazepam, temazepam, triazolam). Several benzodiazepines have the long-acting metabolite N-desmethyldiazepam in common (diazepam, fosazepam, prazepam, clorazepate). Such differences may be very important clinically because pharmacokinetic factors will determine the duration of drug effect and pharmacokinetic parameters constitute the basis for a rational dosage regimen. For the various clinical indications of benzodiazepines the required duration of drug action differs quite fundamentally. In anticonvulsant and anti-anxiety treatment continuous treatment is pursued, so that compounds with long elimination half-lives of parent drug or active metabolites are of advantage. If on the other hand a benzodiazepine is taken as a hypnotic, the duration of action should be restricted to the night, hence a compound with a short elimination half-life is to be preferred. A review is given of the pharmacokinetics of the major benzodiazepines presently available.

[Comparative pharmacokinetics of 5 hypnotic benzodiazepines in healthy volunteers]. / Pharmacocinétique comparée de cinq benzodiazépines hypnotiques chez le volontaire sain.

The authors have studied the pharmacokinetics of the five benzodiazepines: flurazepam, flunitrazepam, nitrazepam, temazepam and triazolam. The pharmacokinetics parameters of these molecules are different and vary according to individual sensitivity. Twelve healthy volunteers were involved in this study (6 males--6 females). The parent drug has been titrated for nitrazepam, flunitrazepam, temazepam, triazolam and the active metabolite of flurazepam, the N-desakylflurazepam (DAF). Half-lifes have been calculated: it is short for the temazepam and triazolam with no accumulation after multiple drug administration. Triazolam has the shortest half-life. Those different results enable to better understand the prescription problem of hypnotics as duration of action must be limited to one night, with no residual effect the day after.