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R Jochemsen

Publications and source records attributed to R Jochemsen.

At least 19 recordsLinked to original sources
PubMed1993

Predictive performance of population pharmacokinetic parameters of tianeptine as applied to plasma concentrations from a post-marketing study.

The predictive ability of population pharmacokinetic parameters of tianeptine, obtained from a mixed effect analysis of pre-marketing pharmacokinetic studies, was evaluated using tianeptine plasma concentrations obtained during a large multi-center post-marketing surveillance study. The mean prediction error was 7.8 ng.ml-1 and the root mean square prediction error was 52.1 ng/ml when initial estimates of population pharmacokinetic parameters were used to predict drug concentrations in one half of the post-marketing data. When the population parameters were revised to reflect the data collected in the first half of the post-marketing study, the mean prediction error was reduced to -3.2 ng.ml-1 and the root mean square prediction error was reduced to 29.5 ng.ml-1. These results suggest that population pharmacokinetic parameters obtained from pre-marketing data may not accurately predict drug concentrations in patients receiving the drug in the post-marketing setting. Once the population parameters are updated to reflect data from the post-marketing period, the predictive ability of the data-base increases, but substantial variability in the prediction error remains.

Adolescent↗
PubMed1993

Development of a population pharmacokinetic database for tianeptine.

Two thousand three hundred and thirty five plasma concentrations of tianeptine from 112 patients enrolled in nine studies of tianeptine pharmacokinetics performed prior to the marketing of the drug were pooled for analysis using mixed-effect modeling. Studies represented a combination of single dose and multiple dosing at steady-state. Tianeptine plasma concentration time data were fit to a two compartment model with first order absorption using the NONMEM computer program. The results of this analysis suggested that alcoholism is associated with significant increase in clearance (124% increase) and volume of the central compartment (161% increase). The volume of the peripheral compartment is significantly lower in women (31% decrease) and in depressed patients (59% decrease). The population mean (interindividual variability) clearance was equal to 0.17 l.h-1 x kg-1 (28.6%), the volume of central compartment was 0.13 l.kg-1 (60.4%), intercompartmental clearance was 0.07 l.h-1 x kg-1 (30.1%), volume of the tissue compartment was 1.17 l.kg-1 (28.3%), and the absorption rate constant was 0.63 h-1 (21.8%). The residual variability was approximately 30% at concentrations expected during clinical use of the drug. Because of the increased clearance, alcoholic patients would be expected to have significantly reduced concentrations during steady-state dosing. These population parameters provide a basis for developing initial dosing recommendations and for performing bayesian evaluations of drug concentrations obtained in post-marketing studies.

Administration, Oral↗
PubMed1993

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.

Acetaminophen↗
PubMed1986

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.

Anti-Anxiety Agents↗
PubMed1985

Central effects during the continuous osmotic infusion of a benzodiazepine (triazolam).

The effects of relatively constant plasma levels of a rapidly eliminated benzodiazepine (triazolam) were studied in young healthy males to determine whether tolerance to certain effects may develop over a relatively short period of time. The drug was given over a period of 30 h (2 days and 1 night) at zero-order rate using a rectal osmotic pump. Performance was measured at 2 hourly intervals during the day and was continuously impaired during the infusion, though there was a rapid recovery when the infusion ceased. All tasks were affected, in particular mental arithmetic and letter cancellation, but there was some improvement in performance during the second day. The normal circadian improvement in performance may have contributed to this effect, but some degree of tolerance to the effect of the drug cannot be excluded. Overnight there was a marked reduction in wakefulness, suppression of slow wave sleep, and delay to the onset and reduction in the duration of rapid eye movement sleep. During the night after infusion there was less slow wave sleep and increased wakefulness. The experimental design may prove useful in the study of tolerance to drugs.

Adult↗
PubMed1984

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.

Adolescent↗
PubMed1983

Assay of midazolam and brotizolam in plasma by a gas chromatographic and a radioreceptor technique.

A gas chromatographic method (GLC) using a capillary column, electron capture (EC) detection and a solid injection system for the determination of midazolam and brotizolam in plasma is described. Furthermore, the application of a radioreceptor technique (RRA), using a dry and stable benzodiazepine receptor preparation and 3H-flunitrazepam as a labelled ligand for the assay of both drugs is presented. A comparison was made between the RRA and the GLC method. For the gas chromatographic method, linear calibration graphs (r greater than 0.995) was obtained in the range of 0.1 -0.5 ng of brotizalam, and 1.0-5.0 ng of midazolam. Differences between duplicates were less than 8%. The relative affinity of the 1-hydroxymethyl and 4-hydroxy metabolites of brotizolam and midazolam were 0.33 and 0.14 respectively for brotizolam and 0.64 and 0.23 for midazolam. Extraction yields of parents drugs and metabolites were similar. Application of the methods to pharmacokinetic studies of the drugs indicated that they were sufficiently sensitive to measure plasma concentrations for at least three times the elimination half-lives. There was a good correlation between results obtained with the gas chromatographic method and those obtained with the receptor technique. Correlation coefficients were 0.94 (based on 37 samples) for brotizolam and 0.99 (based on on 33 samples) for midazolam, and there were no significant differences between pharmacokinetic parameters obtained with the two methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Azepines↗
PubMed1983

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.

Adult↗
PubMed1983

Pharmacokinetics of brotizolam in healthy subjects following intravenous and oral administration.

Pharmacokinetics and bioavailability of brotizolam after i.v. and oral administration were studied in healthy young volunteers. Kinetic parameters after i.v. administration were: volume of distribution 0.66 +/- 0.19 1/kg, total plasma clearance 113 +/- 28 ml/min, distribution half-life 11 +/- 6 min, and elimination half-life 4.8 +/- 1.4 h (mean values +/- s.d.). Kinetic parameters after oral administration were: absorption lag-time 8 +/- 12 min, absorption half-life 10 +/- 11 min, and elimination half-life 5.1 +/- 1.2 h (mean values +/- s.d.). Bioavailability of brotizolam was 70 +/- 22% when calculated by comparing oral and intravenous area-under-curve values, corrected for intra-individual half-life differences. An alternative calculation method, which is relatively independent of large clearance variations, provided a bioavailability of 70 +/- 24% (range: 47-117%).

Administration, Oral↗
PubMed1983

Comparative pharmacokinetics of brotizolam and triazolam in healthy subjects.

Pharmacokinetics of oral brotizolam (0.50 mg) and triazolam (0.50 mg) were studied in healthy young volunteers. The plasma concentration profile of brotizolam can be described as a one compartmental open model with first-order absorption. The absorption of triazolam was less regular and in half of the subjects was not consistent with first-order kinetics. Inter-individual variability in absorption rate (peak times) was larger for brotizolam. Mean peak times were 1.1 +/- 1.0 h for brotizolam and 1.2 +/- 0.5 h for triazolam. Mean peak concentrations were 7.3 +/- 3.1 ng/ml and 5.0 +/- 3.9 ng/ml respectively. The elimination half-life of brotizolam was twice that of triazolam with mean values of 5.0 +/- 1.1 h and 2.6 +/- 0.7 h respectively. There was no correlation between the half-lives of the two drugs. Protein unbound fraction was similar for triazolam and brotizolam with mean values of 9.9 +/- 1.5% and 8.4 +/- 0.7% respectively.

Administration, Oral↗
PubMed1983

Pharmacokinetics of brotizolam in the elderly.

Disposition of brotizolam in patients aged 71-93 years was compared with that of healthy young subjects aged 21-26 years. The mean elimination half-life of brotizolam was about twice as long in the elderly as in the young subjects: 9.3 (4.0-19.5) h and 4.8 (3.1-6.3) h respectively. Increase in elimination half-life was attributable to a decrease in hepatic clearance, i.e. 40 (20-58) ml/min in the elderly and 109 (77-156) ml/min in the young. Volume of distribution and protein binding were the same with mean values of 0.56 (0.45-0.72) l/kg and 9.0 (6.8-11.9) % in the elderly and 0.63 (0.40-0.77) l/kg and 8.4 (7.5-9.4) % in the young. Absorption rate of brotizolam was relatively slow in the elderly with a mean peak time of 1.7 h compared with 1.1 h in the young. Mean bioavailability was almost 70% for both groups. Normalized for body weight and dose (0.25 mg) mean peak concentrations were 247 (137-395) ng ml-1 kg in the young and 343 (251-446) ng ml-1 kg in the elderly. It is unlikely that substantial drug accumulation will occur if elderly patients ingest 0.25 mg brotizolam nightly.

Administration, Oral↗
PubMed1983

Pharmacokinetics of oral brotizolam in patients with liver cirrhosis.

Disposition of oral brotizolam (0.5 mg) was studied in male patients with liver cirrhosis (patients) and in other patients (control) matched for age, weight, smoking and drinking habits. Absorption of brotizolam was relatively rapid in both groups with a median peak time (range) of 1.0 (0.5-2.0) h. Peak concentrations were also similar with median values of 7.1 (3.2-10.7) ng/ml in patients and 9.4 (2.9-19.0 ng/ml) in controls. Elimination half-life was longer in patients than in controls. The median values were 12.8 (9.4-25) h and 6.9 (4.4-8.4) h respectively (P less than 0.01). In two patients hardly any drug elimination was observed, indicating severe impairment of drug metabolizing activity. The prolongation of the elimination half-life was likely to be due to a decrease in clearance (45 ml/min in patients compared with 64 ml/min in controls), and an increase in volume of distribution (0.62 l/kg and 0.39 l/kg respectively). Median values of protein unbound fraction of brotizolam were 9.2 (7.8-10.4) % in controls and 12.4 (10.4-18.9) % in patients. Clearance of unbound drug was 612 ml/min and 380 ml/min respectively.

Administration, Oral↗
PubMed1982

[Comparative pharmacokinetics of 5 hypnotic benzodiazepines in healthy volunteers].

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.

Anti-Anxiety Agents↗