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V W Steinijans

Publications and source records attributed to V W Steinijans.

At least 19 recordsLinked to original sources
PubMed1992

Sample size determination for bioequivalence assessment using a multiplicative model.

In bioequivalence studies Cmax and AUC serve as the primary pharmacokinetic characteristics of rate and extent of absorption. Based on pharmacokinetic relationships and on empirical evidence, the distribution of these characteristics corresponds to a multiplicative model, which implies a logarithmic normal distribution in the case of a parametric analysis. Hence, consideration is given to exact and approximate formulas of sample sizes in the case of a multiplicative model.

Methods↗
PubMed1992

Bronchodilatory effect of inhaled zardaverine, a phosphodiesterase III and IV inhibitor, in patients with asthma.

Zardaverine is a newly developed selective phosphodiesterase III and IV inhibitor. This study investigates the bronchodilatory properties of zardaverine, administered by inhalation. Twelve patients with reversible bronchial obstruction (increase in forced expiratory volume in one second (change FEV1 % predicted) at least 15% after 200 micrograms salbutamol, median age 31 yrs, range 21-54 years) entered the double-blind, crossover study. Four puffs of either zardaverine (total dose 6 mg) or placebo were inhaled at 15 min intervals. Pulmonary function (specific airway conductance (sGaw) and FEV1 was measured by body plethysmography at regular intervals (5 and 12 min after each puff and, in addition, 30, 60, 120, 180 and 240 min after the last puff). Compared to placebo, sGaw and FEV1 increased significantly during the first hour of repeated inhalations, but not during the entire observation period of almost 5 h. The maximum mean difference between zardaverine and placebo for FEV1 was 0.3 l or 12% and occurred approximately 1 h after inhalation of the first puff. In seven patients FEV1 increased by > 15%. The duration of action varied considerably between patients. Three patients complained of side-effects (headache, drowsiness, vertigo, nausea), and one of these dropped out of the study due to vomiting. We conclude that inhalational administration of zardaverine has a modest and short-lasting bronchodilating activity.

Administration, Inhalation↗
PubMed1992

Effect of changing the bioequivalence range from (0.80, 1.20) to (0.80, 1.25) on the power and sample size.

International harmonization of guidelines for bioequivalence assessment has led to a wide acceptance of the multiplicative model for the extent and rate characteristics AUC and Cmax and--in consistency with this--of the bioequivalence range (0.80, 1.25). The effect of this change from (0.80, 1.20) on the power of the two one-sided test procedure and the sample sizes based thereon is investigated as a function of the within-subject coefficient of variation (CV) and the ratio mu T/mu R of expected medians for test and reference. The relative reduction in sample size is practically zero for mu T/mu R < or = 0.9 and then gradually increases as mu T/mu R approaches 1.2. At mu T/mu R = 1, the reduction is up to 20%. For a fixed ratio mu T/mu R this reduction increases with the coefficient of variation, reaching a plateau at a CV of about 25%.

Models, Statistical↗
PubMed1992

Presentation of results from bioequivalence studies.

Based on general guidelines and requirements for the design and analysis of bioequivalence studies, specific recommendations are made for the presentation of results, both in tabular and graphical form. This is done by means of two examples, one of a single-dose study and one of a multiple-dose study. The recommendations in this paper are twofold. Firstly, a complete and rather detailed presentation of results is given, which practically corresponds to the standard of research reports. Secondly, a subset of this is suggested for publication. It gives the essential results for bioequivalence assessment in a standardized form. From an editorial point of view, it would be highly appreciated if the papers submitted for publication were always accompanied by a complete presentation including the individual concentration/time data and the various steps of calculation. This would speed up peer review and ultimately improve and harmonize the standard of bioequivalence publications.

Adult↗
PubMed1992

Sample size determination: extended tables for the multiplicative model and bioequivalence ranges of 0.9 to 1.11 and 0.7 to 1.43.

For the two-period crossover design and a multiplicative model (logarithmic normal distribution) the decision procedure of choice is based on the inclusion of the shortest 90%-confidence interval for the ratio of expected medians for test and reference in the equivalence range. This inclusion rule is equivalent to the two one-sided tests procedure. Sample sizes based on the power of the latter have been given by Diletti et al. [1991] for an equivalence range of 0.8 to 1.25. Corresponding tables for the tighter equivalence range of 0.9 to 1.11 as well as for the wider range of 0.7 to 1.43 are given in this amendment.

Confidence Intervals↗
PubMed1992

Bioequivalence studies: single vs multiple dose.

Bioequivalence of different preparations of the same drug substance has gained considerable importance over the last few years due to increasing generic substitution. The procedure that the manufacturer of the generic test preparation has to show bioequivalence with an appropriate reference preparation is scientifically accepted and laid down in international regulations. However, the necessity of single- vs multiple-dose bioequivalence studies has not been discussed in detail with the exception of the Dutch and US guidelines on sustained-release theophylline formulations, where multiple-dose studies are specifically required. This paper compares the conclusions drawn from single- and multiple-dose studies in the same subjects and recommends appropriate pharmacokinetic characteristics.

Chemistry, Pharmaceutical↗
PubMed1992

A distribution-free procedure for the statistical analysis of bioequivalence studies.

In bioequivalence assessment, the consumer risk of erroneously accepting bioequivalence is of primary concern. In order to control the consumer risk, the decision problem is formulated with bioinequivalence as hypothesis and bioequivalence as alternative. In the parametric approach, a split into two one-sided test problems and application of two-sample t-tests have been suggested. Rejection of both hypotheses at nominal alpha-level is equivalent to the inclusion of the classical (shortest) (1-2 alpha) 100%-confidence interval in the bioequivalence range. This paper demonstrates that the rejection of the two one-sided hypotheses at nominal alpha-level by means of nonparametric Mann-Whitney-Wilcoxon tests is equivalent to the inclusion of the corresponding distribution-free (1-2 alpha) 100%-confidence interval in the bioequivalence range. This distribution-free (nonparametric) approach needs weaker model assumptions and hence presents an alternative to the parametric approach.

Adult↗
PubMed1992

Update on the statistical analysis of bioequivalence studies.

Statistical methods to assess bioequivalence of a test and a reference formulation are reviewed with emphasis on the distribution of bioequivalence characteristics and the consumer risk of erroneously accepting bioequivalence. Among the procedures not exceeding a nominal consumer risk of 5%, the one with an acceptably small producer risk of erroneously rejecting bioequivalence is selected. With the exception of tmax, the following strategy is recommended: a decision in favour of bioequivalence is made if the shortest 90%-confidence interval for the ratio of the expected medians is in the bioequivalence range for the chosen characteristics of rate and extent of absorption. If the assumption of a logarithmic normal distribution is not valid, the analogous nonparametric (distribution-free) 90%-confidence interval, which is also based on the two-sample approach for the sequences reference/test and test/reference, is the procedure of choice. The issue of a modification of the bioequivalence range of 80-120% to other values for bioequivalence characteristics other than AUC (e.g. Cmax) is also addressed. Finally, a decision rule for tmax is presented.

Chemistry, Pharmaceutical↗
PubMed1992

Sample size determination for bioequivalence assessment by means of confidence intervals.

The statistical analysis of bioequivalence assessment has been consolidated in recent years through the work of Schuirmann [1987], Westlake [1988] and Hauschke et al. [1990], and this has been reflected in the CPMP Note for Guidance on Bioavailability and Bioequivalence and in the joint recommendations of the APV (International Association for Pharmaceutical Technology) and ZL (Central Laboratories of German Pharmacists) during a recent workshop in support of EC-Guidelines [Blume et al. 1990]. Since the decision procedure based on the inclusion of the shortest 90%-confidence interval in the bioequivalence range is the procedure of choice, and as this is equivalent to the two one-sided tests procedure, the sample size determination is based on the power of the latter. Following the approach of Phillips [1990] for the additive model, corresponding nomograms for the more relevant multiplicative model are given in this paper for various ratios of the expected means for test and reference and various coefficients of variation.

Confidence Intervals↗
PubMed1992

Sample size determination: extended tables for the multiplicative model and bioequivalence ranges of 0.9 to 1.11 and 0.7 to 1.43.

For the two-period crossover design and a multiplicative model (logarithmic normal distribution) the decision procedure of choice is based on the inclusion of the shortest 90%-confidence interval for the ratio of expected medians for test and reference in the equivalence range. This inclusion rule is equivalent to the two one-sided tests procedure. Sample sizes based on the power of the latter have been given by Diletti et al. [1991] for an equivalence range of 0.8 to 1.25. Corresponding tables for the tighter equivalence range of 0.9 to 1.11 as well as for the wider range of 0.7 to 1.43 are given in this amendment.

Humans↗
PubMed1992

Lack of pharmacokinetic interaction as an equivalence problem.

The demonstration that concomitant administration of drug B does not affect the pharmacokinetics of drug A can be adequately handled as an equivalence problem. Administration of drug A alone serves as reference and simultaneous administration of drugs A and B as test situation. The range of clinically acceptable variation in the pharmacokinetic characteristics of drug A defines the equivalence range. This will usually correspond to the bioequivalence range accepted for the comparison of different formulations of drug A. Equivalence, i.e. lack of pharmacokinetic interaction, is concluded if the 90%-confidence interval for the ratio (difference) of the expected medians for test and reference is entirely within the equivalence range. This decision procedure ensures that the consumer risk of incorrectly concluding "lack of interaction" is limited to 5%. Moreover, the producer risk of incorrectly concluding "interaction" can be controlled by appropriate sample sizes.

Drug Interactions↗
PubMed1992

Presentation of results from bioequivalence studies.

Based on general guidelines and requirements for the design and analysis of bioequivalence studies, specific recommendations are made for the presentation of results, both in tabular and graphical form. This is done by means of two examples, one of a single-dose study and one of a multiple-dose study. The recommendations in this paper are twofold. Firstly, a complete and rather detailed presentation of results is given, which practically corresponds to the standard of research reports. Secondly, a subset of this is suggested for publication. It gives the essential results for bioequivalence assessment in a standardized form. From an editorial point of view, it would be highly appreciated if the papers submitted for publication were always accompanied by a complete presentation including the individual concentration/time data and the various steps of calculation. This would speed up peer review and ultimately improve and harmonize the standard of bioequivalence publications.

Delayed-Action Preparations↗
PubMed1991

The influence of caffeine on the steady-state pharmacokinetics of theophylline.

During this open, two-period crossover study in eight healthy volunteers, 1200 mg anhydrous theophylline was administered as a two-stage infusion during 24 hours on day 6. During one of the 8-day periods, 300 mg caffeine, t.i.d., was administered orally. After the start of the theophylline infusion, plasma concentrations of theophylline and caffeine and urinary excretion of theophylline and four metabolites were determined frequently during 60 hours. With caffeine administration theophylline steady-state concentration and area under the curve increased by 23% and 40%, respectively, whereas the volume of distribution at steady state seemed unchanged. The cumulative urinary excretion of 1-methyluric acid and 1-methylxanthine did not reach a plateau, suggesting a capacity-limiting factor in their formation. Notwithstanding the mutual interference of theophylline and caffeine metabolism, the reduction in apparent total body clearance and elimination rate constant of theophylline by 29% and 31%, respectively, indicated a pronounced influence of concomitant administration of realistic amounts of caffeine.

Administration, Oral↗
PubMed1991

[Chronotherapy concept and the pharmacokinetic validation of a theophylline retard preparation for once-nightly administration (Euphylong)].

Many patients with asthma often experience a deterioration of symptoms at night and in the early morning resulting in sleep disruption and possibly impaired daily performance. A bronchodilator agent which exerts its maximal effect overnight to control nocturnal symptoms, without a worsening of the disease during the daytime, should improve the treatment of asthma. In the case of theophylline, it has been shown in asthmatic patients that a chronotherapeutically optimized formulation which provides the highest serum theophylline concentrations during the critical early morning hours resulted in better airflow levels overnight than the conventional twice daily regimen without loss of airflow in the afternoon. During clinical routine, this chronotherapeutically optimized drug delivery can only be ensured if there is no food interaction. In particular, dose dumping must be excluded. One absolute prerequisite for this is the pH-independent drug release in vitro. In addition to a "state-of-the-art" biopharmaceutic formulation, an easy-to-use guidance for individualizing the theophylline dose should be provided. This in turn is only possible if the concentration/time profiles show good reproducibility between subjects, from day to day, and for different dose levels. Finally, batch-to-batch bioequivalence has to be ensured. It is shown that Euphylong satisfies all of the above requirements.

Asthma↗
PubMed1991

[24-hour lung function in asthmatic patients: chrono-optimal theophylline therapy as once-daily Euphylong administration vs conventional twice-daily administration].

In this study we examined the efficacy and pharmacokinetics of a new chrono-optimized theophylline sustained release preparation for once-daily dosing in the evening for treating bronchial asthma. In a randomized, open crossover study, Euphylong (administered once daily at 2000 hours) was compared with the same dose of a reference preparation (subdivided into two equal doses taken at 800 and 2000 hours). Administration and dosage were in accordance with prior determination of clearance. The patients were outpatients during the first six days of every phase, whereas for the following 24-hour measurement period they were admitted as inpatients for measuring the requisite pharmacokinetic and pharmacodynamic data (PEF, FEV1, PEF 25 = 75, FVC). The theophylline levels remained practically constant for 24 hours under conventional theophylline treatment with twice-daily administration. In contrast, the variations of the theophylline serum levels and the night levels were higher after once-daily dosage of Euphylong, and the daytime levels and especially at the end of the dosage interval were lower. Compared with the standard profile without medication, both sustained release preparations improved the airway obstruction significantly and comparably during a 24-hour period. However, in the early morning hours between 200 and 600 both PEF and FEV1 were significantly higher under Euphylong. Between the improvement of PEF and FEV1 and the theophylline serum concentrations there was a significant correlation between 200 and 600 under Euphylong only. It is concluded that the treatment of asthma with the chrono-optimized once-daily theophylline preparation Euphylong over night is more effective than treatment with a conventional preparation in twice-daily dosage.

Adult↗