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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Pharmaceutical research 13 (1996), S. 453-456 
    ISSN: 1573-904X
    Keywords: absorption rate ; bioequivalence ; Cmax/AUClqc ; Cmax/ AUC ; exposure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The goals were to evaluate the usefulness of Cmax/AUClqc, ratio of the maximum plasma drug concentration to the area under the plasma concentration-time curve to the time of the last quantifiable concentration, in bioequivalence testing and to explore the use of exposure as a replacement for the concepts of rate and extent of drug absorption. Methods. The bioequivalence of products differing in both rate (ka) and extent (F) of absorption was assessed under conditions similar to those encountered in a typical trial. A one-compartment model drug with first-order absorption (rate constant = ka) and elimination was used. Variability was introduced in all model parameters using Monte Carlo techniques. The results were expressed in terms of the probability of declaring bioequivalence in a cross-over trial with 24 subjects using Cmax/AUClqc, AUClqc, and Cmax as bioequivalence measures. Results. The outcome of a bioequivalence trial was shown to depend on the measure. Cmax/AUClqc reflected changes in ka, but not in F. AUClqc showed dependence on F, but virtually no dependence on ka. For Cmax, a 3- to 4-fold increase in ka and a concomittant 20% decrease in F, as well as corresponding changes in the opposite directions, resulted in bioequivalent outcomes. Conclusions. It was concluded that use of Cmax/AUClqc should be discouraged and that defining bioequivalence in terms of rate and extent of absorption has major problems. The goal of bioequivalence trials should be to assure that the shape of the concentration-time curve of the test product is sufficiently similar to that of the reference product. To this end, the use of “exposure” rather than “rate and extent of absorption” concepts is encouraged.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Pharmaceutical research 15 (1998), S. 1292-1299 
    ISSN: 1573-904X
    Keywords: bioequivalence ; intercept metric ; early exposure ; absorption rate ; partial AUC ; experimental design
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To compare the effectiveness of various metrics which evaluate bioequivalence in the early phase of concentration-time profiles. Methods. Two-period crossover trials were simulated with increasing assumed ratios of the true absorption rate constants of the two formulations, and with various kinetic models. Kinetic sensitivities (KS) and standard errors (SE) of the various metrics were recorded and the percentage of trials accepting bioequivalence (the statistical power) was evaluated. The principal metrics included the partial AUC (AUC P) the intercept obtained by linear extrapolation of the ratios of the lower over higher concentrations (C) measured for the two formulations (I L /H), and the ratios of intercepts extrapolated from logarithmic C/ time values of the two products (M log). For comparison, also properties of C maxand an ideally evaluated measure (Id) were determined. Results. M logshowed generally the highest statistical power and KS, and also the largest SE, closely followed by I L /H. Partial AUC exhibited lower power and KS, but also smaller SE than the intercept procedures. The three methods had much higher power, KS and SE than C max. These comparisons were maintained over various kinetic conditions and experimental designs. The effective evaluation of bioequivalence in the early phase of studies is assured with 3 (or more) measurements until the population average peak of the reference formulation. Conclusions. The three principal methods assess bioequivalence very effectively in the early phase of a concentration-time profile. M loghad the highest statistical power, closely followed by IL /Hand then by partial AUC.
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Pharmaceutical research 8 (1991), S. 25-32 
    ISSN: 1573-904X
    Keywords: parent drug ; metabolite ; bioequivalence ; absorption rate ; peak concentration ; time to peak
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The estimation of bioequivalency using metabolite data was investigated for immediate release formulations with drugs exhibiting linear pharmacokinetics and no first-pass effect. This was accomplished by generating parent drug and metabolite plasma level profiles assuming formation and excretion rate-limited pharmacokinetic models with absorption rate constants obtained from bivariate normal distributions and designated random errors. Simulation results indicated that bioequivalence determination using C maxof parent drug and metabolite was independent of the metabolite models as evaluated by confidence interval approach. However, a clear difference with respect to the outcome of bioequivalence evaluation arises depending upon the utilization of C max values for the parent drug and metabolite. The major reason for this disparity was attributed to the minimal effect of the absorption process for the parent drug on the formation of the metabolite. This phenomenon results in an apparent lower intrasubject variability for C max of the metabolite and, in turn, a tighter confidence interval for C max of the metabolite in comparison with the parent drug. The simulated results have been found to be in agreement with the bioequivalency data for acetohexamide, allopurinol, procainamide, and sulindac. In all cases, the interval of the 90% confidence limit for C max of the metabolite is always smaller than that of the parent drug, regardless of the drug pharmacokinetics and the level of error contained in the data.
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Pharmaceutical research 9 (1992), S. 1380-1385 
    ISSN: 1573-904X
    Keywords: bioequivalence ; absorption rate ; partial AUC ; truncated AUC ; peak concentration ; time to peak
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The partial area method was investigated for evaluation of equivalency in the rate of absorption of immediate release formulations. The applicability of the method was demonstrated with four drugs with different pharmacokinetic/pharmacodynamic characteristics. The confidence interval approach currently employed for bioequivalence determinations was applied to the relevant absorption parameters, including C max and partial AUCs. The method was found to be more discriminating than C max and/or T max in the evaluation of the absorption rate of drugs. The cutoff time or point for partial AUC calculation may vary with the type of drug under study, depending on its clinical use and onset of action. The method was shown to be useful in the assessment of rate of absorption in bioequivalence studies.
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Pharmaceutical research 11 (1994), S. 966-974 
    ISSN: 1573-904X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The highest point of the plasma concentration-time profile, C max , is currently used by regulatory agencies to assess the rate of drug absorption after single dose administration of oral products. It is, however, quite insensitive, and a number of new measures of rate have been proposed. Using simulations, several approaches toward measuring rate were tested. A set of model scenarios for drugs with typical mean characteristics and statistical distributions was investigated. Using different kinetic models of disposition, the time course of the concentration in plasma was simulated. Intraindividual and interindividual variability and assay error were modeled using Monte Carlo techniques. The accuracy, precision, and ease of use of the various measures of rate were evaluated by simulating crossover design clinical trials and then determining the probability of declaring bioequivalence as a function of differences in rates of absorption between test and reference formulations. All of the rate measures tested showed a degree of insensitivity to changes in rate and no universally superior measure was found. Indeed, the main conclusion is that the choice of a measure should be based on simulations of the particular situation in a bioequivalence trials.
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Pharmaceutical research 17 (2000), S. 375-380 
    ISSN: 1573-904X
    Keywords: individual bioequivalence ; within-subject variability ; subject-by-formulation interaction ; subgroups
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The FDA has proposed replacing the current averagebioequivalence criterion with population and individual bioequivalence criteriathat consider variances in addition to the difference of averages. Oneof these variances in the individual bioequivalence criterion measuressubject-by-formulation interaction, the extent to which thetest-reference difference varies from person to person. This paper discussesconceptual and statistical issues raised in various publications andpresentations with respect to the presence and estimation of such aninteraction. Methods. We focus on the importance of subject-by-formulationinteraction, an understanding of what is a large interaction, and theassessment of the magnitude of this interaction in bioequivalence studies.Simulation studies, examples from the literature, and data from FDAfiles are used to demonstrate the magnitude of the interaction and itsdistribution under various conditions. Results. The concept of a large interaction is tied to the concept of alarge mean difference. We suggest that an interaction greater than0.15 is a conservative criterion for a large interaction. Magnitudes ofestimated interaction are affected by variability, sample size, and theselection of data sets that pass average bioequivalence. Conclusions. Examples of substantial interactions are beginning toappear. More data is needed before reaching definitive conclusionsregarding the frequency and importance of observed interactions.
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Pharmaceutical research 17 (2000), S. 381-384 
    ISSN: 1573-904X
    Keywords: methylphenidate ; average bioequivalence ; individual bioequivalence ; human ; pharmacokinetics ; replicated design
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine the relative bioavailability of two marketed,immediate-release methylphenidate tablets. The study used a replicatedstudy design to characterize intrasubject variability, and determinebioequivalence using both average and individual bioequivalencecriteria. Methods. A replicated crossover design was employed using 20subjects. Each subject received a single 20 mg dose of the reference tableton two occasions and two doses of the test tablet on two occasions.Blood samples were obtained for 10 hr after dosing, and plasma wasassayed for methylphenidate by GC/MS. Results. The test product was more rapidly dissolved in vitro and morerapidly absorbed in vivo than the reference product. The mean Cmaxand AUC(0 − ∞) differed by 11% and 9%, respectively. Using anaverage bioequivalence criterion, the 90% confidence limits for theLn-transformed Cmax and AUC(0 − ∞), comparing the two replicatesof the test to the reference product, fell within the acceptable range of80–125%. Using an individual bioequivalence criterion the test productfailed to demonstrate equivalence in Cmax to the reference product. Conclusions. The test and reference tablets were bioequivalent usingan average bioequivalence criterion. The intrasubject variability of thegeneric product was greater and the subject-by-formulation interactionvariance was borderline high. For these reasons, the test tablets werenot individually bioequivalent to the reference tablets.
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Pharmaceutical research 11 (1994), S. 715-722 
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; bioequivalence ; extent of absorption ; power analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The determination of the area under the concentration–time curve (AUC) is the method most commonly used by regulatory agencies to assess extent of drug absorption after single-dose administration of oral products. Using simulations, several approaches toward measuring the actual area, in whole or part, were tested. In addition, the performance of the peak concentration (C max), usually taken as a measure of the rate of absorption was assessed evaluating extent. Model scenarios for drugs with typical mean characteristics and statistical distributions were investigated. Using different kinetic models of disposition, the time course of the drug concentration in plasma was simulated. Intraindividual and interindividual variability and assay error were modeled using Monte Carlo techniques. The accuracy, precision, and ease of use of the various measures of extent were evaluated, and statistical power analyses were performed. Among the measures tested, the most reliable were the AUC computed up to the time of the last quantifiable concentration, without extrapolation, and C max. However, being also sensitive to rate, C max as a measure of extent is of limited potential.
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Pharmaceutical research 12 (1995), S. 700-708 
    ISSN: 1573-904X
    Keywords: bioequivalence ; rate of absorption ; rate of availability ; parent drug ; metabolite ; linear pharmacokinetics ; first-pass
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Simulations were conducted to address the question of whether metabolite data are required for bioequivalence evaluation of immediate release formulations with drugs exhibiting linear pharmacokinetics and first-pass effect. Plasma level-time profiles were generated for parent drug and metabolite using relevant rate constants obtained from a bivariate normal distribution and designated random error. Simulation results showed that the need for metabolite data (Cmax) in the assessment of bioequivalence depends on the relative variability between the absorption process of the drug and first-pass route for metabolite(s). The importance of metabolite Cmax data in the evaluation of rate of availability is clearly demonstrated for drugs with a high degree of intra-subject variation in the first-pass metabolism compared to the absorption process of the drug. Under such conditions, a wider confidence interval was found for the metabolite rather than parent drug. Opposite results were obtained when the intra-subject variance was high for drug absorption relative to first-pass effect. Discrepancies were observed for the scenarios in which the elimination pathway of the metabolite is more variable than the absorption process of the drug. The simulation results were in agreement with real bioequivalence data. It is thus recommended that, in the absence of the information on the relative variability of absorption and first-pass process, both parent drug and metabolite data be included for documentation of bioequivalence, should the metabolite(s) play an important role in the determination of efficacy and safety of the drug.
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Pharmaceutical research 15 (1998), S. 399-404 
    ISSN: 1573-904X
    Keywords: bioequivalence ; partial AUC ; absorption rate ; experimental design ; crossover trials
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine favourable sampling conditions for assessing bioequivalence by the comparison of partial AUCs in the early phase of concentration-time profiles. Methods. Two-period crossover trials were simulated. They assumed a wide range of the ratios of absorption rate constants of the test (T) and reference (R) formulations (kaT/kaR). Averages and standard deviations of the corresponding ratios of simulated partial AUCs (AUCpT/AUCpR) were determined together with the statistical power of assessing bioequivalence, i.e., the percentage of simulated trials in which bioequivalence was declared. Results. The power for stating bioequivalence was high when AUCP was recorded until the earlier rather than the later of two peaks in each subject. Similarly, power was comparatively high when AUCP was measured until the time of the reference peak instead of multiples of this time. Power was high also when AUCp was determined until the fixed true, population mean time of the reference formulation instead of multiples of this time. The pattern for the kinetic sensitivity parallelled that found for the power, while the standard deviations changed generally in the opposite direction. Conclusions. The effectiveness (power) of evaluating bioequivalence in the early phase of concentration-time profiles by partial AUCs generally decreases when the duration for measuring the metric is extended. Among the investigated designs, determination of partial AUCs until the earlier of two peaks in each subject is the most powerful.
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