PubMed · 9279874
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T N Tozer, W W Hauck. 1997. Cmax/AUC, a commentary.. https://doi.org/10.1023/a%3A1012128623213
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OBJECTIVES: there is considerable uncertainty about the underlying cause of decreased intestinal calcium absorption that occurs in postmenopausal women. In a previous study, estrogen treatment did not result in an increased intestinal calcium absorption using strontium as a marker. A possible explanation could be that the calcium/strontium load given to the women was too high ( approximately 600 mg Ca), which might result in an insensitive test with respect to the possible stimulation of active strontium transport by estrogen. Therefore, the purpose of this study was to reinvestigate the effect of estrogen on active intestinal strontium absorption using a load of 2.5 mmol of strontium only. METHODS: the effect of estrogen on intestinal strontium absorption was measured in eight normal postmenopausal women. The study included two baseline strontium absorption tests, which were performed with an interval of 10 days for calculating the within subject variation (SER). Thereafter the effect of 2 months of estrogen treatment on intestinal strontium absorption was assessed. Fractional absorption (FC(240)) and the area under the concentration time curve (AUC) 4 h after an oral strontium load of 2.5 mmol were calculated. RESULTS: the within subject SER of FC(240) and AUC(0-240) were 2.3+/-0.76 and 1.2+/-0.41, respectively. FC(240) and AUC(0-240) of strontium were unchanged after treatment with estrogen. CONCLUSIONS: in normal postmenopausal women, we did not find a modulating effect of short-term treatment with a (supra) physiological dose of estrogen on intestinal calcium absorption as measured by the strontium absorption test.
Pharmacokinetic measurements provided by subjects to each of two formulations of a drug have a joint distribution that can be characterized by parameters reflecting scale and correlation as well as location. The bioavailability of the formulations can be expressed in terms of the means of the marginal distributions, their means and variances, or the marginal means and variances and the joint correlation. These expressions correspond, respectively, to 'average', 'population', and 'individual' bioequivalence when the joint distribution of the measurements is bivariate normal. Current proposals for assessing the degree of bioequivalence of two formulations are based on statistics that are composites of variance components and squares of expected mean differences from a mixed linear model. There are technical and practical issues associated with these proposals, particularly that they require more complicated designs than the familiar 2x2 cross-over. This paper describes an alternative approach that can be applied with standard 2x2 cross-over designs, and that provides evaluations of population and individual bioequivalence that should be adequate for all practical clinical purposes. The approach is based on easily computed correlation and regression coefficients whose statistical properties under normality are well known and for which non-parametric and robust alternatives exist when normality cannot be assumed. The approach yields conclusions consistent with those obtained by the current proposals when applied to data sets supplied by the FDA. In the cases where the conclusions do not match, the new approach appears to be more consistent with the data.
A bootstrap-type hypothesis test procedure for assessing individual (or population) bioequivalence between two drug formulations is suggested in a draft guidance from the United States Food and Drug Administration (FDA). The purpose of this article is to study the unknown properties of this test procedure and propose some improved test procedures. We find that: the FDA's bootstrap computation is not correct; the power of the FDA's test can be very low; the use of the REML method suggested in the draft guidance does not have any advantage over the use of simpler methods such as the moment method; and the method of sample size determination in the draft guidance is inappropriate. We study the size and power of different bootstrap test procedures and suggest a method for sample size determination. It is our hope that this article will draw some attention to further research in this area, and eventually a satisfactory statistical method can be implemented for assessing individual (or population) bioequivalence.