[Simulation of bioequivalence study on the base of dissolution curves]. / Bioekvivalencia vizsgálat szimulációja kioldódási görbék alapján.

A computer method based on the in vitro dissolution of drug preparations has been elaborated for the estimation of bioequivalence. The method generates a "dissolutaion surface" from the parameters of time (X-axis), from pH (Y-axis) and from the dissolved amount (A) in % of the drug. This dissolution surface allows the determination of the general dissolution curve of the test and reference preparations. By supposing that the absorption rate constant is known from the literature, the change of the amount of dissolved drug as the function of time can be determined. On the base of this function the maximum amount of the dissolved drug in the gastrointestinal tract and the AUC can be calculated. and the test/reference ratio can be determined. In the case of linear pharmacokinetics these ratios are identical to the ratios of parameters that can be calculated in the circulation. By generating parameters between the allowed biological limits the dissolved drug-time curves of "volunteers" in the necessary number are created with the randomly generated "residence times" and their confidence intervals can be determined, i.e., on the base of dissolution curves bioequivalence can be estimated.

Gas chromatography nitrogen phosphorous detection (GC-NPD) assay of tofisopam in human plasma for pharmacokinetic evaluation.

Tofisopam (1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine) has been shown to be an effective anxiolytic agent in the wide-ranging clinical practice. A high sensitive gas chromatography nitrogen phosphorous detection (GC-NPD) bioanalytical method was developed and validated for the purpose of pharmacokinetic study of tofisopam. A liquid-liquid extraction method was used for the sample preparation. The mean recovery for tofisopam was 69.8% and the inter- and intra-day precision values were well below the 15% limit established for bioanalytical methods. A similar compound, girizopam was used as internal standard. The assay was linear in the 5-500 ng/ml range corresponding to therapeutically relevant plasma levels. The concentrations of the compound were measured in the plasma samples of 12 healthy male volunteers and the pharmacokinetic parameters were determined from the plasma concentration-time data. A rapid absorption and distribution, relatively short biological half-life and considerable inter-individual variation in the plasma concentration levels of parent compound were the main characteristics of the pharmacokinetics of tofisopam. According to these results, the new (GC-NPD) bioanalytical method proved to be capable of measuring concentration of tofisopam in human plasma and was successfully applied in a single dose pharmacokinetic study.

Influence of food on the oral bioavailability of deramciclane from film-coated tablet in healthy male volunteers.

The effect of a high-fat meal on the oral bioavailability of deramciclane 30 mg tablet was evaluated in 18 healthy male volunteers in a randomised, single dose, two-way crossover study. The drug was administered following an overnight fast or a standardised high-fat breakfast. The plasma concentrations of deramciclane and N-desmethylderamciclane were determined by using a validated HPLC-MS -MS/MS method. An effect of food on the bioavailability was indicated if the 90% confidence interval (CI) for the ratio of geometric means of fed and fasted treatments was not contained in the equivalence limit of 0.8-1.25 for AUC and C(max). The ratios of the mean C(max) and AUC(0-infinity) values of deramciclane were 1.24 (90% CI 1.12-1.38) and 1.31 (90% CI 1.21-1.41) in fed versus fasted subjects, which overlapped but exceeded the equivalence limit. In contrast to the parent compound, the 90% CI of the mean ratios for AUC(0-infinity) and C(max) of N-desmethylderamciclane were within the predefined range. The 24 and 31% increase in C(max) and AUC(0-infinity) of deramciclane, respectively, under fed condition is modest and probably has no clinical significance since it is relatively small compared to the inter-individual variability of these parameters.

Studies of the side chain cleavage of deramciclane in rats with radiolabelled compounds.

The pharmacokinetics of deramciclane and especially the fate of its side chain were studied in rats after oral treatment, using (3)H- and (14)C-labelled (ring- or side chain labelled) deramciclane and (14)C-dimethylamino-ethanol ((14)C-DMAE) radioisomers. The labelled compounds were admixed and the total radioactivities of both labels were simultaneously determined. The data obtained from the analysis of the plasma concentration-time curves revealed that an intensive cleavage (30-40%) of the side chain occurred at the ether bond. The core of deramciclane, carrying the ring label, was almost completely eliminated during 24 h, while the elimination of the side chain was very slow (t(1/2)(beta): 99 h). The side chain residue most probably represents dimethylamino-ethanol, but the presence of dimethylglycine (DMG) cannot be excluded. The AUC(0-infinity) and the MRT values of DMAE were found to be much higher than those of the parent compound. In addition to the plasma levels, the time related changes of the tissue concentrations of the radioisomers of deramciclane were analysed both in the brain and the hypophysis. The concentration-time curves have shown similar characteristics to those of the plasma, but higher concentrations were reached in both organs (the highest in the hypophysis). It is postulated that the low rate of formation and elimination of the metabolite(s) (DMAE or DMG) indicates that, due to their endogenous nature, they can be incorporated into choline/acetylcholine or protein synthesis.