Biomedical subjects
Publications and source records attributed to H P Wijnand.
It is demonstrated how complete nonparametric, cumulative probability distributions for Mann-Whitney/Wilcoxon's nonparametric, two-sample test can be constructed based on algorithms published earlier in this journal. These procedures provide cumulative probabilities for all possible rank sums in the nonparametric two-sample test. Separate programs for MS(PC)-DOS and Macintosh computers are offered.
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Updates are given of the earlier published MS-DOS programs BIOEQV37, BIOPAR37 and BIOEQNEW for the statistical analysis of bioequivalence studies. The updates are named BIOEQV52, BIOPAR40 and BIOEQNEW, respectively. Modifications and improvements in the updated programs are discussed. Calculations of statistical power for two-period crossover studies are now based on Schuirmann's two one-sided tests procedure. It is demonstrated that good approximations of power can be obtained by Student's t-statistic. This not only applies to the equations published elsewhere for the 'additive model', but also to hitherto unpublished equations for the 'multiplicative model'.
Hauschke et al.'s non-parametric bioequivalence procedure for treatment effects and some aspects of computer implementation, among them Meineke and De Hey's algorithm and a recursive algorithm, are explored. For studies with up to sixty subjects, a table of indices of the ranked intersubject-intergroup mean ratios or differences is given, to establish non-parametric 90% confidence intervals. It is shown that non-parametric analysis is not limited to treatment effects: it can also be applied to period and sequence effects. This extended procedure can be seen as the non-parametric analogue of analysis of variance on two-period cross-over studies. A FORTRAN program (BIOEQNEW) incorporating Meineke and De Mey's algorithm is presented. This program provides non-parametric point estimates for treatment and period effects, 90% and 95% confidence intervals for test-versus-reference treatments, the 95% confidence interval for periods and a test on sequence effects, so that it can also be used for other than bioequivalence studies. BIOEQNEW can handle ratios ('multiplicative model') as well as differences ('additive model'). It optionally provides the complete non-parametric posterior probability distribution for treatment ratios or differences, so that Schuirmann's 'two one-sided tests procedure' can also be performed in a non-parametric way.
The results obtained with Meineke and De Mey's algorithm for posterior probability distributions in the nonparametric evaluation of two-period cross-over bioequivalence studies are critically discussed. Suggestions for improvement of their program NEWPARM are given. It is shown that this program in its present form cannot handle the results from bioequivalence studies in which more than 15 subjects participated. For larger study sizes, conversion to a more powerful programming language capable of handling large three-dimensional arrays, is mandatory. An alternative algorithm, allowing large sample sizes to be analysed nonparametrically without program conversion, is offered. A general bioequivalence program written by the author, into which this alternative algorithm is implemented, has been in use by a number of pharmaceutical companies and drug regulatory agencies since February 1990; its most recent update is Version 3.7 (BIOEQV37.EXE) of October 1990.
In a cross-over study increasing doses of protamine hydrochloride (20-100 mg) or placebo were administered to six groups of four healthy male volunteers each, following a single intravenous dose of 3200 anti-Xa units of Org 10172. No neutralising effects were observed on the Org 10172 induced changes in the bleeding time, prothrombin time and thrombin time. A small and statistically not significant temporary decrease in anti-Xa activity was observed after doses of 80 and 100 mg protamine chloride. The anti-thrombin activity was dose-dependently and partly irreversibly neutralised by protamine chloride to a maximum of approximately 60%. This neutralisation correlated with the observed shorter prolongation of the thrombin time. The thrombin-generation inhibition activity was for approximately 35% neutralised by protamine chloride doses of 60-100 mg.
1. In a cross-over study a new low molecular weight heparinoid Org 10172 was administered to 12 elderly male and female volunteers. It was well tolerated and no adverse effects occurred. 2. The absolute bioavailability of Org 10172 as measured by plasma anti-Xa activity, glycosaminoglycuronans with no affinity to antithrombin III (NoA-GAG) and thrombin generation inhibiting activity approached 100% in both sexes. 3. The half-life of elimination of its anti-Xa activity (19.2 +/- 6.1 h) was similar to that found previously in young volunteers. Org 10172 was further characterised by a rapid disappearance from the circulation of its anti-thrombin activity (t1/2 1.8 +/- 0.6 h) and of the NoA-GAG (t1/2 3.5 +/- 2.1 h). 4. Its thrombin generation inhibiting activity was of intermediate duration (t1/2 elimination 6.2 +/- 4.0 h).
In fitting the one-compartment open model with first-order processes to empirical data, it has frequently been found for single-dose administration that the absorption and elimination rate constants approach each other. If these rate constants tend to be equal, such combinations are impossible to solve with the general model equation. In 1968, Dost published a special model function by which the problems associated with the general model function can be circumvented. No solution, however, has been published for multiple-dose functions with the one-compartment model in which the absorption and elimination rate constants are equal. For a two-compartment open model with first-order processes, similar problems arise if the absorption and exponential distribution rate constants approach each other. Although this type of problems is often encountered in pharmacokinetic curve-fitting to empirical data, no exact solution has been published. Equations are given for multiple-dose administration with the one-compartment open model in which the absorption and elimination rate constants are equal, and for single-dose and multiple-dose administration with the two-compartment open model in which the absorption and exponential distribution rate constants are equal. Included are criteria to decide whether the new or the classical model functions should be applied in the case of a two-compartment open model.
Nandrolone decanoate (Deca-Durabolin) was injected intramuscularly into healthy volunteers. One group of females received one injection of 100 mg and three groups of males received one injection of 200 mg, two repeat injections of 100 mg or four repeat injections of 50 mg respectively. The serum levels of nandrolone (19-nortestosterone) were determined by radioimmunoassay and used to estimate pharmacokinetic parameters. The following pharmacokinetic parameters were found: a mean half-life of 6 days for the release of the ester from the muscular injection depot into the general circulation; a mean half-life of 4.3 h for the combined processes of hydrolysis of nandrolone decanoate and of distribution and elimination of nandrolone; a mean nandrolone serum clearance of 1.55 1 X h-1 X kg-1. The half-life of hydrolysis of nandrolone decanoate in serum was of the order of one hour or less. The data are consistent with linear kinetics.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
For bioequivalence testing of pharmaceutical formulations of the same drug entity, it is not sufficient to carry out an analysis of variance on the characteristic to be evaluated (e.g., area under the plasma level vs time curve, half-life of elimination, time to plasma-peak level, plasma peak level) and to establish 'classical' 95% confidence intervals for the difference or the ratio of the characteristic concerned. In the past 10 years, several approaches have been proposed as an aid in decision-making: Westlake's 95% intervals, Rodda and Davis' probabilities, Fluehler's posterior probability histograms and the evaluation of the residual variation coefficient. A survey of these approaches is given, together with a discussion of their merits, their differences and their similarities. It is recommended that the final evaluation should be supported by probability density plots, which facilitate easy understanding of the differences and similarities between the various approaches. A bioequivalence study with two types of oral tablets containing bepridil, a new anti-anginal drug, is used as an example. Computer programs are presented, which enable the user to easily apply the various approaches in order to meet requirements of regulatory agencies.
A survey is given of the methods for the determination of the absolute bioavailability for drug substances with long elimination half-lives. All methods depend on the assumption of linear pharmacokinetics. Emphasis is laid on Urso and Aarons' regression method of truncated areas-under-the-curve (AUC) to obtain estimates of the absolute bioavailability, F, and the absorption rate constant, ka, without obeying the otherwise general rule of following blood or plasma levels for at least three times the terminal half-life. It is shown by simulation when the linear and when the logarithmic trapezoidal rule is to be used for the calculation of the AUC. Two PC-programs for the regression method of truncated areas are presented: one program (SIMF&KA.EXE) simulates, based on tentative pharmacokinetic parameters, whether a blood sampling scheme, together with the precision of the analytical assay, is adequate to obtain accurate and precise estimates of F and ka; the method is insensitive to large variations in the tentative value of the elimination half-life. The other program (ESTF&KA.EXE) provides estimates of F and ka, with standard deviations of the estimates, from empirical data.