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  • 1
    ISSN: 1573-904X
    Keywords: bioequivalence ; absorption rate ; Tmax ; absorption process rate ; measurement theory ; inference
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Peak drug concentration (Cmax) measures the extremity of drug exposure and is a secondary indicator of the extent of absorption after area under the concentration time curve (AUC). Cmax serves as the indicator of absorption rate in bioequivalence (BE) studies in the US (1). The use of Cmax, not the time to Cmax(Tmax), as the metric to assess absorption rate causes erratic inferences in BE studies, and incorrect conclusions for some. We can improve BE efficiency (i.e., get the answer right the first time), by properly analyzing the time to Cmax(Tmax) instead of Cmax. Methods. We have previously redirected attention to Tmax as the unconfounded absorption rate variable, instead of Cmax, and have called for equally spaced sampling times during the suspected absorption phase to improve the performance of the rate metric (2). Equal spacing converts Tmax easily into a count variable and we illustrated an appropriate statistical analysis for counts. This paper provides some measurement theory concepts to help judge which is the more appropriate analysis, and also provides parametric confidence limits for Tmax treatment differences. Three separate BE studies are then analyzed by both methods. Results. By focusing on the differences in conclusions, or inferences, this paper identifies three major issues with the current FDA "recommended” analysis of BE studies. First, Cmax, a continuous variable peak-height or extent measure has usurped Tmax's function and performs erratically as a substitute measure for the rate of absorption. Second, Tmax, should be analyzed as a discrete attribute, not as a continuous variable. Third, since several extent measures (AUC, Cmax), not one, are actually being analyzed, an adjustment for multiple testing is mandatory if we are to maintain the size of the test at the desired α level (13), and not inadvertently use a narrower bioequivalence window than is intended. These actions all can have serious unintended consequences on inferences, including making inappropriate ones.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1573-904X
    Keywords: bioequivalence ; absorption rate ; Tmax ; discrete count variable ; Poisson distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. While peak drug concentration (Cmax) is recognized to be contaminated by the extent of absorption, it has long served as the indicator of change in absorption rate in bioequivalence studies. This concentration measure per se is a measure of extreme drug exposure, not absorption rate. This paper redirects attention to Tmax as the absorption rate variable. Methods. We show that the time to peak measure (Tmax), if obtained from equally spaced sampling times during the suspected absorption phase, defines a count process which encapsulates the rate of absorption. Furthermore such count data appear to follow the single parameter Poisson distribution which characterizes the rate of many a discrete process, and which therefore supplies the proper theoretical basis to compare two or more formulations for differences in the rate of absorption. This paper urges limiting the use of peak height measures based on Cmax to evaluate only for dose-dumping, a legitimate safety concern with, any formulation. These principles and techniques are illustrated by a bioequivalence study in which two test suspensions are compared to a reference formulation. Results. Appropriate statistical evaluation of absorption rate via Tmax supports bioequivalence, whereas the customary analysis with Cmax leads to rejection of bioequivalence. This suggests that the inappropriate use of Cmax as a surrogate metric for absorption rate contributes to the unpredictable and uncertain outcome in bioequivalence evaluation today.
    Type of Medium: Electronic Resource
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