Sándor Drabant

In vitro simulation of food effect on dissolution of deramciclane film-coated tablets and correlation with in vivo data in healthy volunteers

The in vitro dissolution profiles of deramciclane 30 mg film-coated tablets, an acid-labile new 5-HT receptor antagonist, were studied under simulated fasting and fed conditions. Artificial gastric juice with pH adjusted to that of fasting conditions was applied either alone or after adding different dietary components. The use of the USP dissolution apparatus II (paddle method) showed that the presence of dietary components has markedly affected the amount of unchanged drug dissolved. As a similar tendency had been observed in food-effect studies in healthy volunteers, cumulative area under the curve (AUC(cum)) for both fed and fasting conditions were compared and an in vitro--in vivo correlation (IVIVC) was evaluated. A linear relationship was established between logarithmic in vivo blood sampling time and in vitro dissolution time assigned to equal AUC(cum) ratios (AUC(cum, fed)/AUC(cum, fasting)). Despite its limitations, in vitro modelling of in vivo conditions might help provide a base for predicting in vivo drug behaviour.

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 Tmax was 2–4 h. The elimination half‐life increased from about 20 h to about 32 h with the increasing dose. Nevertheless, the AUC0–∞ 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. Cmax was reached at about 6 h. The AUC0–48 h for the N‐desmethyl metabolite was about one third of the AUC0–∞ of the parent compound and the ratio remained constant at each dose level. Deramciclane was safe, and was well tolerated at each dose level. Copyright

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.

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 (fmax(meas))- The mean of the terminal half-life was 70.0 ± 23.1 h (fi/2/i) The area under the plasma concentration-time curve (AUC) calculated by the kinetic equation (AUCcaic) was 4814 ±1172 and by the trapezoidal rule (AUCtrap) was 4612 ± 1357 (ng/ml) h.

Tofisopam inhibits the pharmacokinetics of CYP3A4 substrate midazolam

Interaction between tacrolimus, a substrate of the cytochrome P450 3A4 enzyme (CYP3A4) [1], and the 2,3benzodiazepine anxiolytic tofisopam has been reported after kidney transplantation. Tofisopam increased 2to 5-fold the plasma concentration of tacrolimus, leading to clinically relevant renal function impairment. In vitro findings have indicated that CYP3A4 is responsible for tofisopam metabolism [2], and tofisopam inhibits the human recombinant CYP3A4 activity (IC50=0.8 μM) [3]. To evaluate the clinical relevance of the CYP3A4 inhibiting effect of tofisopam, a clinical study was performed using alprazolam as a hepatic CYP3A4 probe drug [4]. Tofisopam slightly increased the area under the plasma concentration time curve from zero to infinity (AUC) and elimination half-life (t1/2) of alprazolam after a single oral dose and decreased the clearance, indicating modest inhibition of hepatic CYP3A4. The magnitude of inhibition was not sufficient to explain the pharmacokinetic interaction between tofisopam and tacrolimus. Tacrolimus is a substrate of the intestinal CYP3A4 [5]; therefore, interaction between the two drugs may occur at the intestinal level. A pharmacokinetic/pharmacodynamic drug– drug interaction study was performed to evaluate the effect of tofisopam on CYP 3A4 activity at the intestinal level. Midazolam was selected as a probe drug because the small intestine is a major place for presystemic CYP3A-medited metabolism of midazolam after oral administration [6], which was clearly demonstrated by the discovery of the metabolites during the anhepatic period of liver transplantation [7]. Sixteen Caucasian healthy male subjects were enrolled to this open-label, two-period, single-treatment sequence study after written informed consent was obtained. The study protocol was approved by the Hungarian National Institute for Pharmacy, the Clinical Pharmacological Ethical Committee of Scientific Health Council. The study was performed at the Drug Research Center, Balatonfüred, Hungary. Subjects received a single dose of 7.5 mg midazolam on study period 1. After a 1-week washout period, subjects received 100 mg of tofisopam three times a day for 9 days. On day 7 of tofisopam treatment, subjects received a single 7.5 mg dose of midazolam 1 h after the morning dose of tofisopam. Midazolam plasma concentrations were measured for 48 h after single dosing and for 96 h when midazolam was coadministered with tofisopam. Plasma levels were determined using the capillary gas chromatography-mass spectrometric method. Alprazolam was used as the internal standard. The lower limit of quantification for midazolamwas 0.5 ng/ml. The pharmacokinetic parameters for midazolam were determined by standard noncompartmental method using KineticaTM Ver. 4.02 validated software (InnaPhase, Champs sur Marne, France). The 90% confidence interval (90% CI) around the geometric mean of the test (midazolam-tofisopam cotreatment)/reference (midazolam treatment) ratio was calculated for maximum plasma concentration (Cmax), the area under the plasma concentration time curve from zero to infinity (AUC), the elimination half-life (t1/2), and for apparent oral clearance Eur J Clin Pharmacol (2008) 64:93–94 DOI 10.1007/s00228-007-0397-y

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

SummaryIn 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−∞, AUC0−t, Cmax, Cmax/AUC0−∞, tmax) 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−∞ 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−∞ 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.

Effect of tofisopam on the single-oral-dose pharmacokinetics and pharmacodynamics of the cyp3a4 probe drug alprazolam

Interaction between tacrolimus, a substrate of the cytochrome P450 3A4 enzyme (CYP3A4), and the 2,3benzodiazepine anxiolytic tofisopam has been reported in kidney transplant patients. Tofisopam increased the plasma concentration of tacrolimus, leading to aggravation of patients’ renal function. In vitro findings with human recombinant CYP3A4 have indicated that tofisopam inhibits the activity of the enzyme (IC50=0.8 μM), but its effect was an order of magnitude weaker than that of ketoconazole (IC50=0.03 μM) [1]. A pharmacokinetic/pharmacodynamic drug-drug interaction study was done to evaluate the effect of tofisopam on CYP3A4 activity, using alprazolam as a probe drug. Sixteen Caucasian healthy male volunteers were enrolled in this double-blind, randomised, two-way crossover study after each gave written informed consent. The study protocol was approved by the Hungarian Clinical Pharmacological Ethical Committee of the Scientific Health Council and the local ethics committee of the Drug Research Center, Balatonfüred. Subjects received 100 mg of tofisopam three times a day (the highest recommended dose in clinical practice) or matched placebo for 9 days in a random order. On day 7 of each treatment period, a single 0.5-mg dose of alprazolam was administered 1 h after the morning dose of tofisopam. Alprazolam plasma concentrations were measured for 72 h using a validated capillary gas chromatographic-mass spectrometric method. The internal standard was midazolam in the assay. The lower limit of quantification for alprazolam was 0.1 ng/ml. The interassay precision and accuracy were 8.6–10.6% and 1.3–4.3%, respectively. The pharmacokinetic parameters for alprazolam were determined by a standard noncompartmental method using Kinetica version 4.02 validated software (InnaPhase, Champs sur Marne, France). The effect of tofisopam on the pharmacokinetics of alprazolam was evaluated using an analysis of variance model appropriate for the underlying crossover design. The 90% confidence interval (CI) about the geometric mean ratio of the two treatments for maximum plasma concentration (Cmax), the area under the plasma concentration time curve from zero to infinity (AUC), the elimination half-life (t1/2), and the apparent oral clearance (CL/F) were calculated and expressed as a percentage of the reference (alprazolam with placebo) treatment. To assess the possible pharmacodynamic interaction between the two drugs, cognitive tests (immediate and delayed word recall, digit symbol substitution test) and subjective ratings of drug effects were performed. Fifteen subjects completed the study. One subject was withdrawn because of intercurrent disease after the first treatment period. There was a significant but slight 124% (90% CI 115– 135%) and 121% (90% CI 113–135) increase in the AUC and t1/2 of alprazolam, respectively, and an 81% (74–87%) decrease in the CL/F of alprazolam during concomitant administration with tofisopam compared with placebo. The Cmax of alprazolam was not affected by tofisopam (Table 1). No significant differences in the performance on the pharmacodynamic tests were observed. The results of the study indicate that tofisopam only modestly inhibits hepatic CYP3A4 activity. This effect does not sufficiently explain the mechanism of the pharmacokinetic interaction between tofisopam and tacrolimus. Several studies indicate that in addition to hepatic CYP3A4, tacrolimus is a substrate of the intestinal CYP3A4 and P-glycoprotein (PgP) drug transporter [2]. Interaction between the two drugs may occur at the S. Drabant (*) . M. Tóth . A. Bereczki . J. Bajnógel . J. Tömlö EGIS Pharmaceuticals Ltd., Keresztúri út 30-38, Budapest, Hungary, 1106 e-mail: clinpharm.rd@egis.hu Tel.: +36-1265-5774 Fax: +36-1265-5758

Comparative pharmacokinetics of new theophylline preparations as Egifilin® 200 mg and 400 mg retard tablets after single dose in healthy volunteers

AbstractPharmacokinetic properties of Egifilin® retard tablets (containing 200 or 400 mg of theophylline, EGIS Pharmaceuticals Ltd., Budapest, Hungary) were investigated in 12 healthy volunteers (six women, six men). Pharmacokinetic analysis was performed according to a one-compartment open model. The retard nature of both 200 and 400 mg tablets could be demonstrated. Comparison of the pharmacokinetic curves of women and men indicated that there was no sex difference in the pharmacokinetics of two retard tablets.Egifilin retard tablets ensured plasma levels for almost 30 hr after single drug intake with an extremely long retard plateau between 6 and 30 hr. For study purposes, an improved rapid HPLC-UV analytical method (less than 3.5 min chromatogram) has been elaborated for the determination of theophylline in human plasma. The range of the calibration is 0.6–18 μg/ml.