Absolute bioavailability and bioequivalence of glibenclamide (Semi-Euglucon N).

The absolute bioavailability of HB 420 (a new pharmaceutical form of glibenclamide) was investigated in comparison with an i.v. infusion of glibenclamide and also in comparison with HB 419 (Semi-Euglucon) on a group of 10 healthy volunteers with the aid of a highly specific bioanalytical detection method. A comparison of the dose-corrected areas under the concentration-time curves yielded an absolute bioavailability of 102% for HB 420. The relative bioavailability of HB 419 to HB 420 was 73%. This resulted in a bioequivalent dosage relationship of 2.5 mg HB 419 to 1.75 mg HB 420. It could be experimentally confirmed on further 10 healthy volunteers that 1.75 mg HB 420 (identical with Semi-Euglucon N) and Semi-Euglucon (containing 2.5 mg HB 419) are bioequivalent with respect to the absorbed quantity of active agents. The differences in absorption rate between the new and the old form did not lead to relevant differences in the glucose profile and the release of insulin, so that the two forms can be regarded as being pharmacodynamically equivalent. The median for the terminal elimination half-life for glibenclamide was 1.38 hours (min. 0.65, max. 4.64 hours), the total clearance was 100 ml/min and the steady-state distribution volume was 7.3 l (0.1 l/kg). On the basis of half-life, it can be expected that the elimination of the unchanged substance will be virtually complete within 10-12 hours. During long-term therapy, however, it cannot be ruled out that in some diabetics cumulation could occur, the cause of which cannot be explained by the data presented.

Evaluation of bioavailability by different methods.

Demonstration of bioavailability (or bioequivalence) is a condition for marketing of a drug product, unless a waiver is granted. Biovailability is usually based on some statistical evaluation of three parameters, the area under the concentration-time curve, AUC, the peak concentration, Cmax, and the peak time, tmax, obtained for both the test drug product and the standard, using a crossover design with 12 to 24 subjects. The three biovailability parameters can be obtained by various mathematical procedures, and may vary according to the procedure selected and the operator's decision. The purpose of this study was to compare two of the most widely used evaluation procedures, a curve-fitting method (NONLIN 84) and the linear trapezoidal rule, with a recently developed compartment model and operator input independent procedure, KINPAK. As the model drug, theophylline was used after single dose administration (experimental sustained-release tablet vs elixir) and multiple dose administration (experimental sustained-release tablet vs Theodur). Theophylline exhibits not only large interindividual, but also intraindividual, variations in its disposition. Accepting the postulate that biovailability is a biologic quality control test, KINPAK not only recognizes outliers of concentration-time data within a sequence of individual data sets but also outliers within a sample of individuals. Neither for the single dose study nor for the multiple dose study were significant differences found between the various evaluation methods. This cannot be guaranteed for other studies. KINPAK offers primarily the following advantages, standardized computation of all pharmacokinetic parameters derivable from a concentration-time course without making arbitrary model assumption, more or less questionable data points are recognized, omitted, but listed, automatic tabulation and/or plotting of raw data and evaluation results without transcription errors, ready for submission to regulatory agencies.

KINPAK--a new program package for standardized evaluation of kinetic parameters.

Concept and basic routines of a new program package (KINPAK) for standardized evaluation of kinetic parameters are described. This new program is not based on compartmental analysis. Instead the experimental data sequence is fitted by flexible regression functions adequate for concentration-time curves. From fitted regression curves the relevant biologic parameters are calculated. These parameters express mainly the geometric properties of the curve. The fitting and parameter calculation is governed by numerous plausibility checks which guarantee feasible and reproducible results without arbitary intervention by the user. The program is mainly designed for use in industrial research and for presentation to administrative authorities. The methods are standardized and concieved to be performed as closed job. Tables and graphs can be generated for entire experimental series and are ready for use as documentation required by regulatory agencies.

Simulation studies of errors of parameter estimates in pharmacokinetics.

Pharmacokinetic parameters are indispensable for the development and evaluation of drugs. Therefore, they are required by international drug agencies and may influence relevant decisions. Their determination from experimental results is only possible with statistical errors. For the estimation of these errors only approximative procedures are available. A widespread approximation (information inequality) is based on specific assumptions which are invalid in practice. Erroneous estimations of unknown amount may consequently result. Alternative methods more adaptable to reality are simulation techniques with random numbers. This technique was used to calculate the statistical variability of parameter estimates for the usual compartment models. The results were compared with the variation of the parameter estimates from a descriptive model function recently developed. Adequate curves were predefined by appropriate parameter sets. Around these curves, a random generator simulated 500 data sequences. Fitting with the appertaining model function resulted in 500 sets of estimated parameters. The statistical behavior of the parameter estimates was investigated. The parameters computed by the fitting procedure--in the compartment models the rate constants--showed a large variation so that an estimate from a single data sequence does barely reproduce the "true" value of the parameter. In contrast, the parameters derived from the geometric properties of the fitted curves (e.g., area under curve, time and height of maximum) showed considerable less variation. As far as these investigations allow a conclusion, the latter parameters seem to be sufficiently reliable for practical purposes.

Pharmacokinetics and metabolism of isosorbide-dinitrate after intravenous and oral administration.

The bioavailabilities of a conventional and two slow release 20 mg isosorbide dinitrate (ISDN) formulations were compared after oral administration in a three way cross-over study in 8 male volunteers. In a further group of 6 male volunteers the pharmacokinetics and metabolism of ISDN were investigated after intravenous infusion of a median dose of 14.1 mg for 2.5 h. A new analytical procedure was developed for the determination of isosorbide-5-mononitrate-2-glucuronide (IS-5-MN-2-Glu) and of isosorbide (IS). Kinetic data analysis on a molar basis was performed by the program package KIN-PAK providing model independent parameters. The median elimination half-lives of ISDN, IS-5-MN, IS-2-MN and IS-5-MN-2-Glu were 0.7, 5.1, 3.2 and 2.5 h, respectively. The systemic clearance of ISDN was 3.71/min and the distribution volume 2521 (3.1 l/kg). Apart from IS-5-MN-2-Glu, with a renal clearance of 5.9 l/min which suggested substantial glucuronidation in the kidney, the renal clearances of ISDN, IS-5-MN, IS-2-MN and the corresponding amounts excreted were negligible. 27.8% of the administered ISDN was excreted as IS-5-MN-2-Glu (8.7%) and IS (19.1%). Calculations based on the two mononitrate metabolites formed from ISDN showed an incomplete recovery of 84.1%, leading to the assumption that a simultaneous denitration to IS must have occurred. The rate of denitration at each nitro group in ISDN was almost twice as high as for the same position in the corresponding mononitrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of metipranolol in normal man.

The pharmacokinetic parameters of deacetyl metipranolol were determined after i.v. infusion of increasing doses (6-25mg) in 17 normal volunteers. In a second cross-over trial, deacetyl metipranolol 10 and 20mg were infused in a further 10 subjects, and in a third trial another 20 volunteers received metipranolol 40mg orally. Metipranolol is very rapidly and completely deacetylated in man, so all pharmacokinetic data refer to deacetyl metipranolol, which was assayed by gas chromatography-mass spectrometry. The pharmacokinetic analysis was performed using a recently developed model, using a volume of distribution which is variable with time. The following data were obtained after oral administration: (mean values); lag-time 7.3 min; tmax 50 min, invasion half-life 6.3 min; elimination half-life 3 h; urinary excretion of unchanged drug approximately 4% of the dose. The experiments with infusion of increasing doses, as well as the cross-over study with 10 and 20mg i.v., showed dose-linearity of the kinetics. The respective mean half-lives of elimination were 2.6, 2.9 and 2.8 h. The mean total, renal and extra-renal clearances amounted to 1237 ml/min, 149 ml/min and 1068 ml/min, respectively. The distribution coefficient was 3.5 l/kg, and protein binding amounted to 70% within the range of therapeutic concentrations. Absolute bioavailability was found to be approximately 50% by several different evaluation procedures. Thus, the pharmacokinetic profile of metipranolol shares features of both the lipophilic and the hydrophilic groups of beta-blocking agents.

Estimation of absorption ratios and their variation for orally administered drugs.

Differences in the plasma concentrations of drugs after oral administration are caused by two main factors: variation in absorption ratios and in the distribution processes in the body. A new method for the dissection of both types of factors is discussed. The method uses a reference regression of the AUC-values to the corresponding values after intravenous infusion of graded doses. The reference regression is estimated from an appropriate trial. Deviation of the determined AUC-values from the regression curve afford an estimate of the residual variance due to varying distribution volumes or similar random biological effects. For the estimation of absorption ratios after oral administration the drug is given orally to another sample of subjects and their AUC-values are calculated. The deviation of these AUC values due to the above mentioned random effects are simulated using the residual variance of the reference regression, and are subtracted from the observed AUC-values. Then, the differences in the corresponding absorbed doses are transformed by inverting the reference regression. From these doses the empirical distribution function and statistical parameters (e.g. quantiles) are determined. The method has the advantage that no restrictive assumptions are required, such as first order processes, dose linearity, homogeneity of variance or normal distribution of absorption ratios. Its applicability to substances with qualitative differences in their pharmacokinetics is demonstrated by appropriate examples.

Pharmacokinetics of intravenous and oral isosorbide - 5 - mononitrate.

The pharmacokinetics of isosorbide-5-mononitrate (IS-5-MN) has been studied in two groups of healthy volunteers after oral (n = 20) and intravenous (n = 11) administration of 20 mg, which had previously been proved to be as effective as 20 mg sustained-release isosorbide dinitrate (ISDN). IS-5-MN in serum was measured by gas chromatography using capillary columns. The kinetic calculations were carried out with a newly developed model, which assumes a virtual volume of distribution dependent on time. IS-5-MN is rapidly (invasion half-life 4.1 min) and completely absorbed from the gastro-intestinal tract without any first pass metabolism. The maximum concentration of 480 micrograms/l was reached 1.2 h after oral administration of 20 mg. The substance was distributed throughout the total body water (distribution coefficient: 0.62), and was eliminated with a terminal t1/2 of 4.1 and 4.6 h after oral and intravenous administration, respectively. Total body clearance was 115ml/min. Thus, IS-5-MN is unlike ISDN with respect to the absence of first-pass metabolism and an 8-times longer half-life. The consequences for therapy are discussed.

Effects and pharmacokinetics of isosorbide dinitrate in normal man.

18 subjects were given isosorbide dinitrate (ISDN) 5 mg sublingually and serum concentrations of ISDN, 2-isosorbide mononitrate (2-ISMN) and 5-isosorbide mononitrate (5-ISMN) were measured, as well as changes in digital plethysmographic amplitude, heart rate, ECG, blood pressure and Schellong's test. ISDN was rapidly absorbed and metabolized, having an elimination half-life of 29 min. Its metabolites 2-ISMN and 5-ISMN had longer half-lives of 1.75 and 7.6 h respectively. The amplitude of the alpha-wave of the digital plethysmograph did not change significantly either in the pre-drug period or after placebo administration. It increased within 4 min of administration of ISDN, and reached a maximum after 14 min; the effect lasted for about 2 h. ISDN lowers blood pressure and increases heart rate in most volunteers, but in 3 of the 18 subjects severe hypotension occurred, accompanied by severe, reversible bradycardia, which was probably due to vagal reflexes initiated by the markedly diminished ventricular enddiastolic volume (LVEDV) and pressure (LVEDP). No correlation could be demonstrated between the serum concentration of ISDN and/or its vasoactive metabolites and changes in plethysmographic amplitude.

Clinical and pharmacological investigations of the new saluretic azosemid.

Ple 1053 (Azosemid) is a diuretic which resembles furosemide chemically and in its mode of action. When administered intravenously, Ple 1053 was approximately 5 times more potent on a weight basis than furosemide, its dose-response relationship was closer and the slope was steeper. After oral administration Ple 1053 and furosemide were approximately equal in potency. However, the effect of Azosemid in healthy subjects was relatively prolonged and abrupt peaks did not occur.