Comparative bioavailability of alpha-methyldopa normal and film tablet formulations after single oral administration in healthy volunteers.

In a single dose, randomized, cross-over study, with one week of wash-out period, the relative bioavailability of Dopegyt tablets containing 250 mg alpha-methyldopa (AMD) and Presinol film tablets with identical active ingredient content was examined in 24 healthy volunteers. Since technologically two completely different preparations (a film-tablet and a non-film-tablet) having significantly different in vitro dissolution were to be compared, both preparations were compared to a third one, AMD solution (Dopegyt solution) with 250 mg/50 ml concentration. Plasma concentrations of the drug were measured for 24 hours post-dose, applying HPLC with fluorometric detection. Pharmacokinetic parameters calculated from individual data (AUC0-infinity, AUC0-t, Cmax, Cmax/AUC0-infinity, t(max)) were evaluated statistically. Wilcoxon's nonparametric test and the four-way variance analysis could not detect any significant difference at the usual a=95% probability level in these pharmacokinetic parameters of the two tablet preparations. For AUC0-infinity at the 90% probability level, the confidence interval was 0.883-1.237 (with an estimated geometric mean of 1.045), for the test/reference ratio of Dopegyt and Presinol tablets, thus the two preparations proved to be bioequivalent. The relative bioavailability of Dopegyt (test preparation) and Presinol (reference preparation) calculated from the AUC0-infinity values was 116.7+/-56.7% that also confirmed bioequivalence. The results of all the applied statistical tests suggest that Dopegyt and Presinol can be considered as bioequivalent preparations.

Pharmacokinetics and safety of deramciclane during multiple oral dosing.

UNLABELLED: Deramciclane is a new putative non-benzodiazepine-type anxiolytic compound. It is a selective serotonin 5-HT(2A) and 5-HT(2C) receptor antagonist and has also inverse agonist properties. The aim of this study was to reveal the pharmacokinetics and tolerability of deramciclane during repeated oral dosing in healthy male volunteers. SUBJECTS, MATERIAL AND METHODS: A randomized double-blind, placebo-controlled design was used. The study had three consecutive groups that received first a single oral dose of 10, 30 and 60 mg of deramciclane followed by twice a day administration for seven days. The total number of subjects was 28. The pharmacokinetic parameters were calculated for a single dose and after repeated administration. Tolerability was assessed by monitoring safety laboratory variables, electrocardiogram, heart rate, blood pressure and adverse events. RESULTS: The steady-state was reached during the seven-day administration. The pharmacokinetics of deramciclane was dose-proportional at steady-state at each dose level. Deramciclane accumulated about three-fold during repeated administration. The relative bioavailability of deramciclane increased about 1.4-fold compared to that of a single dose at each dose level. The mean elimination half-life of deramciclane for 10, 30 and 60 mg doses prolonged from 24.3, 20.9 and 22.9 h after a single dose to 30.5, 25.6 and 28.7 h at steady-state, respectively. Only few adverse events were reported, all mild and transient in nature. The most frequently reported adverse drug reactions were tiredness and headache. There were no deramciclane-induced changes in the clinical chemistry or hematology variables, blood pressure, heart rate or in electrocardiogram. CONCLUSIONS: In conclusion, the pharmacokinetics of deramciclane is linear over the dose range of 10 - 60 mg at steady-state. The slight non-linearity within the dose levels during repeated administration of seven days was regarded as clinically irrelevant. Deramciclane was safe and well tolerated up to doses of 60 mg b.i.d. for seven days.

The single dose pharmacokinetics and safety of deramciclane in healthy male volunteers.

The pharmacokinetics and tolerability of a new putative non-benzodiazepine type anxiolytic compound deramciclane was studied in two consecutive studies. An open dose-escalation design was used to study doses from 0.2 to 50 mg in 18 healthy male volunteers. In the second study doses from 50 to 150 mg were investigated in 14 healthy males in a double-blind, placebo-controlled, dose escalation study. Deramciclane was rapidly absorbed from the GI-tract and T(max) was 2-4 h. The elimination half-life increased from about 20 h to about 32 h with the increasing dose. Nevertheless, the AUC(0-infinity) values increased linearly within the studies over the dose ranges of 3-50 and 50-150 mg. However, the increase was more than the ratio of the dose over the total dose range of 3-150 mg. Therefore, non-linear pharmacokinetics of deramciclane at high doses cannot be excluded. N-desmethyl deramciclane, which is the active metabolite of deramciclane, was determined in plasma. C(max) was reached at about 6 h. The AUC(0-48 h) for the N-desmethyl metabolite was about one third of the AUC(0-infinity) of the parent compound and the ratio remained constant at each dose level. Deramciclane was safe, and was well tolerated at each dose level.

Different absorption profiles of deramciclane in man and in dog.

We have studied the dog model for predicting the oral absorption of deramciclane, a novel anxiolytic compound, as a model acid-labile drug. The absorption profile of deramciclane was studied in man and beagle dogs after administration of conventional capsules and enteric coated tablets. Absorption in dogs pretreated with pentagastrin or saline was also studied after administration of conventional capsules. The in-vitro stability of deramciclane was determined over the pH range 1.2-6.0. The rate of degradation of deramciclane increased ten-fold as the pH was reduced from 2.1 to 1.2 (t 1/2 beta (elimination half-life) 9 h and 39 min, respectively). Deramciclane was stable at pH > or = 3. The two formulations were bioequivalent in dogs and there were no significant differences between pharmacokinetic parameters measured for dogs pretreated with pentagastrin or saline. In man the mean relative bioavailability and Cmax (peak plasma concentration) for the conventional capsules were approximately 75% and 83% of those for the enteric coated tablets (P = 0.0004 and P = 0.0031, respectively). This was probably because of degradation of deramciclane at lower pH of man's stomach compared with that of the dog. Pentagastrin was probably unsuccessful in reducing gastric pH and thus no change in absorption was observed. It is concluded that the absorption of deramciclane, and possibly other acid-labile drugs, cannot be predicted by use of the dog model.

[Role of food interaction pharmacokinetic studies in drug development. Food interaction studies of theophylline and nifedipine retard and buspirone tablets]. / Etelinterakciós farmakokinetikai vizsgálatok helye és jelentósége a gyógyszerfejlesztésben. Teofillin retard, nifedipin retard és buspiron tabletták ételinterakciós vizsgálata.

Due to several mechanism, meals may modify the pharmacokinetics of drug products, thereby eliciting to clinically significant food interaction. Food interactions with the drug substance and with the drug formulation should be distinguished. Food interaction of different drug products containing the same active ingredient can be various depending on the pharmaceutical formulation technology. Particularly, in the case of modified release products, the food/formulation interaction can play an important role in the development of food interaction. Well known example, that bioavailability of theophylline can be influenced in different way (either increased, decreased or unchanged) by concomitant intake of food in the case of different sustained release products. The role and methods of food interaction studies in the different kinds of drug development (new chemical entity, modified release products, generics) are reviewed. Prediction of food effect response on the basis of the physicochemical and pharmacokinetic characteristics of the drug molecule or formulations is discussed. The results of three food interaction studies carried out the products of EGIS Pharmaceuticals Ltd. are also reviewed. The pharmacokinetic parameters of theophyllin 400 mg retard tablet were practically the same in both fasting condition and administration after consumption of a high fat containing standard breakfast. The ingestion of a high fat containing breakfast, increased the AUC of nifedipine from 259.0 +/- 101.2 ng h/ml to 326.7 +/- 122.5 ng h/ml and Cmax from 34.5 +/- 15.9 ng/ml to 74.3 +/- 23.9 ng/ml in case of nifedipine 20 mg retard tablet, in agreement with the data of literature. The statistical evaluation indicated significant differences between the pharmacokinetic parameters in the case of two administrations (before and after meal). The effect of a high fat containing breakfast for a generic version of buspiron 10 mg tablet and the bioequivalence after food consumption were studied in a single-dose, three-way (test and reference products administered after consumption of standard breakfast, as well as test product in fasting condition), cross-over, food effect bioequivalence study. According to the results, the test product--which, in a former study proved to be bioequivalent with the reference product in fasting state--is bioequivalent with the reference product under feeding conditions and the food intake influenced the pharmacokinetics of the test tablets.

Food interaction pharmacokinetic study of cordaflex 20 mg retard filmtablet in healthy volunteers.

The aim of the present study was to investigate the effect of food consumption on the pharmacokinetics of Cordaflex 20 mg retard filmtablet in healthy volunteers through measuring nifedipine plasma levels by an HPLC-ED method both after fasting and food ingestion. The food interaction pharmacokinetic study of Cordaflex 20 mg retard filmtablet was carried out in 12 healthy male volunteers treated with a single dose of the preparation both after fasting and after food ingestion, in a crossover design allowing 1 week of wash-out period between the 2 treatments. Nifedipine concentration of plasma samples were determined by an isocratic HPLC-ED method [Horvai et al. 1994] with robotic sample processing [Horváth et al. 1995, 1996]. The pharmacokinetic parameters (AUC0-infinity, AUC0-t, Cmax, MRT) were analyzed by calculating 90% confidence interval for logarithmic transformed test/reference ratio values, and Schuirmann's statistical tests, the tmax and HVD values were analyzed by Wilcoxon's nonparametric statistical test. The above statistical tests of the present food interaction study indicated significant differences for each one of the respective pharmacokinetic parameter pairs calculated for treatments after fasting and after food ingestion. On the basis of the above findings and also by comparing the mean pharmacokinetic curves, it was evident, that, in agreement with the data of literature [Kleinbloesem et al. 1993, Schall et al. 1994], food ingestion increased the relative bioavailability and maximum plasma concentration (Cmax). Considering the average of the parameter values and also the respective statistical tests, it was also apparent that the time to maximum plasma concentration (tmax), the mean residence time (MRT), and the half-value duration (HVD) all decreased significantly upon the effect of food ingestion.

Pharmacokinetic and bioequivalence study of two gemfibrozil preparations.

A comparative pharmacokinetic study has been performed in 19 healthy male volunteers in a single-dose, randomized, two way cross-over design with two preparations of gemfibrozil (CAS 25812-30-0) capsules each of them containing 300 mg active ingredient. The test preparation was Innogem 300 mg capsule. The plasma concentration of gemfibrozil was determined by a validated HPLC-UV analytical method. The statistical comparison of individual pharmacokinetic parameters (AUC0-16, AUC0-oc Cmax, tmax) of the two capsule preparations was performed by three-way analysis of variance (ANOVA), Wilcoxon's, Westlake's, Schuirmann's and Hanck-Anderson's method as well as by the calculation of confidence intervals on the ratio of test/reference. The relative bioavailability of the test preparation with respect to the reference preparation in terms of the AUC0-oc was 104.06 +/- 21.61%. No statistically significant difference was found between the pharmacokinetic parameters, calculated from plasma concentration-time curves, indicating that the two preparations were bioequivalent.

Pharmacokinetics of panomifene in healthy volunteers at phase I/a study.

Panomifene (PAN) /E/-1,2,-diphenyl-1-[4-[2-(2-hydroxyethylamino)-ethoxy]-phenyl]-3, 3,3-trifluoropropene is a new original Hungarian compound and is a tamoxifen (TMX) analog. In the phase I/a study presented here the human tolerance, pharmacokinetics and endocrine effects of a single oral dose of panomifene were evaluated in healthy, post-menopausal, female volunteers. As to the dose escalation, pharmacokinetic studies were carried out at doses of 24, 48 and 96 mg in two volunteers, and 120 mg in one volunteer. To find a suitable dose or dose range, for further evaluation of the drug detailed pharmacokinetics were performed at a selected dose level (24 mg) in 10 volunteers. The pharmacokinetic study showed considerable interindividual variability of the parameters, and only a medium correlation between dose and AUC (r=0.876). At the selected dose level (24 mg p.o.) the peak concentration of the plasma was 67.7 +/- 17.4 ng/ml (Cmax(meas)), the time to peak was 3.6 +/- 1.8 h (t[max(meas)]). The mean of the terminal half-life was 70.0 +/- 23.1 h (t(1/2beta)). The area under the plasma concentration time curve (AUC) calculated by the kinetic equation (AUCcalc) was 4814 +/- 1172 and by the trapezoidal rule (AUCtrap) was 4612 +/- 1357 (ng/ml) h.

Human bioequivalence study of a new nifedipine containing retard filmtablet after single and repeated administration.

A clinical pharmacokinetic bioequivalence study with two retard filmtablet preparations, both containing 20 mg of nifedipine (CAS 219829-25-4) was carried out. The investigated test preparation was Cordaflex 20 mg retard filmtablet. The pharmacokinetic parameters were determined after single and repeated administration in 15 and 16 healthy male volunteers, respectively, in open, randomised studies of cross-over design. Plasma levels of nifedipine were determined by HPLC with electrochemical detection using a robotic sample preparation technique. Statistical comparison of the pharmacokinetic parameters (AUC0-infinity, AUCss, tau tmax, Cmax, Css,min, Css,av, MRT, etc.) calculated from plasma concentration-time curves by ANOVAlog, confidence interval, Schuirman's, Westlake's, Anderson's and Wilcoxon's tests, furthermore the comparison of the clinical results did not show any significant difference between the two preparations. It is concluded that the two preparations are bioequivalent after repeated administration.

[Human pharmacokinetic study of nerisopam and its n-acetyl metabolite]. / A nerisopam és N-acetil metabolitjainak humán farmakokinetikai vizsgálata.

It was established during the human phase I study of nerisopam, a new anxiolytic drug, that nerisopam (EGIS-6775) shows two, while N-acetyl metabolite (EGIS-7649) shows one compartmental pharmacokinetic behaviour. Acetylation of nerisopam is polymorph, so that volunteers belonging into slow or fast acetylating group show significantly different plasma concentration. Observed pharmacokinetic differences are primarily manifested in the absorption phase, and not in the elimination one. Accordingly, slow acetylators have higher nerisopam levels, while fast acetylators possess higher metabolite levels. Elimination phase is practically parallel for both compounds. At the same time, significant differences are found in the AUC and Cmax values. Nerisopam is rapidly absorbed, but N-acetyl metabolite is appeared especially fast in the blood. Our consideration is, that nerisopam undergoes significant "first-pass" metabolism process, the extent of which is different between the two acetylator phenotypes.

Food interaction study of a new theophylline (Egifilin) 200 and 400 mg retard tablet in healthy volunteers.

The aim of the present food interaction study was to determine the blood plasma levels of theophylline upon the administration of new Egifilin 200 and 400 mg retard tablets, either on an empty stomach or after meal, and to make comparative pharmacokinetic evaluation in 26 healthy volunteers. For determination of the plasma levels of theophylline an improved isocratic HPLC-UV method was used in the concentration range of 0.1-18 micrograms/ml. The mean pharmacokinetic curves obtained with 200 and 400 mg tablets before and after meal were in good agreement also on the basis of statistical evaluation, although, as usual with theophylline, the evaluation of the individual pharmacokinetic curves indicated great variations. The pharmacokinetic parameters (AUCzero-t, AUCzero-infinity, HVD, MRT, Cmax, tmax) calculated for Egifilin 200 and 400 mg retard tablets were analyzed by ANOVA, ANOVAlog, Wilcoxon, and Schuirmann statistical tests as well as by the confidence interval calculation. As it was found, under the circumstances of the present food interaction study, food consumption did not have a biologically significant effect on the pharmacokinetic parameters of either the 200 or the 400 mg Egifilin retard preparations.

[Bioanalysis of gemfibrozil. Comparative human pharmacokinetics of 300 mg of gemfibrozil-containing Innogem and Lopid capsules]. / A gemfibrozil bioanalitikája Innogem és Lopid 300 mg kapszulák humán összehasonlító farmakokinetikai vizsgálata.

Comparative pharmacokinetic study was performed in 19 healthy male volunteers in a single-dose, randomized, two way cross-over trial on two preparations of gemfibrozil (Innogem and Lopid capsules) each of them containing 300 mg active ingredient. After administration either the test preparation (Innogem, EGIS Pharmaceuticals Ltd.,) or the reference preparation (Lopid, Parke-Davis) in human, the plasma concentration of gemfibrozil was determined by validated HPLC-UV (225 nm) bioanalytical method. After the relatively simple liquid-liquid extraction of the plasma samples the separation was carried out under isocratic condition on Nucleosil 10, C-18 column. On the basis of the validation process the limit of quantitation (LOQ), of the HPLC method was 250 ng/0.5 ml. All the validation parameters fell within the internationally accepted range. The comparison of individual pharmacokinetic parameters (AUC0-16, AUC0-infinity Cmax, tmax) of the two capsule preparations was accomplished by three-way analysis of variance (ANOVA), Wilcoxon's, Westlake's, Schuirmann's and Hauck-Anderson's method as well as by the calculation of confidence intervals on the ratio of test/reference values. The relative bioavailability of Innogem with respect to Lopid 300 mg capsule for AUC0-infinity was 104.06 +/- 21.61%. No statistically significant difference was found in the clinical results and between the pharmacokinetic parameters calculated from plasma concentration-time curves indicating that the two gemfibrozil preparations were bioequivalent after single administration.

[Endocrine effect of a new anti-estrogen compound (EGIS-5650, panomifene) in healthy volunteers: phase I/a study]. / Az antisztrogén hatású új vegyület (EGIS-5650, panomifene) endokrin hatásairól egészéges önkénteseken: fázis I/a vizsgálat.

Influence of a new Hungarian antiestrogen, panomifene (PAN) was investigated on some hormone levels of 10 postmenopausal healthy women during a partially double-blind placebo controlled phase I/a study. Following a single oral administration of PAN serum estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin (PROL) levels were measured by RIA at two selected dose levels: 12 mg and 120 mg. The low dose (12 mg) results in an increased E2 level in some cases probably due to the intrinsic estrogenic (agonistic) character of the drug. The high dose (120 mg) seems to have a strong antiestrogenic (antagonistic) action. FSH and LH changed within the normal postmenopausal range at both doses, PROL slightly decreased at 12 mg dose level. During the 14-day follow up, the 120 mg PAN considerably suppressed the PROL secretion proving the antiestrogenic character of the "high" dose. PAN seems to be a safe tamoxifen analogue, the single oral dose of which does not exert any noteworthy (pathogenic) side effect on some hormone levels of healthy women.