Bioequivalency absorption rate

For generic bioequivalence the generic manufacturer would be expected to use the same chiral material as the innovator (most probably a racemic mixture or pure active isomer, though it is possible that in some rare instances the innovator might have discovered a valid reason for using some mixture of R and S other than 50/50). Thus, as with development bioequivalency, it would not normally seem necessary to use stereoselective assays for the separate determination of R and S isomers. However, one can conceive of possible situations where clinically significant differences in R-to-S ratios could be caused by even relatively small differences in absorption rate [6,7]. 

Diltiazem Functional relationship between PK and PD parameters is described by hysteresis loops with a clockwise rotation. This cannot be explained in the classical way by the time lag between central and effect compartments. The model of down regulation/toler-ance development is proposed as a result supported by the finding that the shape of the hysteresis is dependent on the absorption rate of diltiazem, calculated as mean input time. Acute tolerance to dilitazem develops at least with the electrophysiologi-cal action of diltiazem after oral application and that the extent of tolerance development increases when decreasing its absorption rate. Bioequivalence assessment of diltiazem is possible using PD parameters however, because PK/PD relationships are influenced by the absorption rate, extent parameters may be misinterpreted when rate parameters of the test formulations are different... 

Bioequivalence Scientific basis on which generic and brand-name drugs are compared. To be considered bioequivalent, the bioavailability of two products must not differ significantly when the two products are given in studies at the same dosage under similar conditions. Some drugs, however, are intended to have a different absorption rate. The FDA may consider a product bioequivalent to a... 

Subsequent studies in our laboratory have reproduced the above results and demonstrated that similar formulations will produce similar R S ratio vs. time profiles (plots C in Fig. 4), whereas dissimilar formulations produce R S ratio vs. time profiles that appear to differ in subtle but discernible ways (plots B in Fig. 4). Since differences in the 1 S ratio vs. time profiles were seen even as the formulations met the rigorous bioequivalency criteria for each of the four analytes, the R S ratio may be a powerful tool in helping to identify and understand the interaction between absorption rate and differential saturation of metabolic enzymes. 

Endrenyi L, Fritsch S, Yan W. Cmax/AUC is a clearer measure than Cmax for absorption rates in investigations of bioequivalence. Int J Clin Pharmacol Ther Toxicol 1991 29 394-399. 

Macheras P, Symillides M, Reppas C. An improved intercept method for the assessment of absorption rate in bioequivalence studies. Pharm Res 1996 13 1753-1756. 

Tozer, T. N. et ah, Absorption rate vs. exposure which is more useful for bioequivalence testing Pharm. Res., 13 453 56, 1996. 

The assessment of bioequivalence is based on 90% confidence intervals for the ratio of the population geometric means (test/reference) for the parameters under consideration. This method is equivalent to two one-sided tests with the null hypothesis of bio-inequivalence at the 5% significance level. Two products are declared bioequivalent if upper and lower limits of the confidence interval of the mean (median) of log-transformed AUC and Cmax each fall within the a priori bioequivalence intervals 0.80-1.25. It is then assumed that both rate (represented by Cmax) and extent (represented by AUC) of absorption are essentially similar. Cmax is less robust than AUC, as it is a single-point estimate. Moreover, Cmax is determined by the elimination as well as the absorption rate (Table 2.1). Because the variability (inter- and intra-animal) of Cmax is commonly greater than that of AUC, some authorities have allowed wider confidence intervals (e.g., 0.70-1.43) for log-transformed Cmax, provided this is specified and justified in the study protocol. 

Boni, J.P. Korth-Bradley, J.M. Richards, L.S. Chiang, S.T. Hicks, D.R. Benet, L.Z. Chiral bioequivalence effect of absorption rate on racemic etodolac. Clin. Pharmacokinet. 2000, 39, 450-469. 

Bioavailability, Bioequivalence, and Pharmacokinetics. Bioavailabihty can be defined as the amount and rate of absorption of a dmg into the body from an adrninistered dmg product. It is affected by the excipient ingredients in the product, the manufacturing technologies employed, and physical and chemical properties of the dmg itself, eg, particle size and polymorphic form. Two dmg products of the same type, eg, compressed tablets, that contain the same amount of the same dmg are pharmaceutical equivalents, but may have different degrees of bioavailabihty. These are chemical equivalents but are not necessarily bioequivalents. For two pharmaceutically equivalent dmg products to be bioequivalent, they must achieve the same plasma concentration in the same amount of time, ie, have equivalent bioavadabihties. 

Also, if conversion of drug to active metabolite shows significant departure from linear pharmacokinetics, it is possible that small differences in the rate of absorption of the parent drug (even within the 80-125% range for log transformed data) could result in clinically significant differences in the concentration/ time profiles for the active metabolite. When reliable data indicate that this situation may exist, a requirement of quantification of active metabolites in a bioequivalency study would seem to be fully justified. 

Id. at 355(j)(2)(A)(iv). Bioequivalence means that the rate and extent of absorption of the generic drug is not significantly different from the rate and extent of absorption of the listed drug t hen administered at the same dosage. 

BioavaUabUity and bioequivalence are related terms but they can be confused. Bioavailabihty as defined earlier is also known as absolute bioavailability and is simply the fraction of the administered dose that reaches the systemic circulation it is therefore defined only in terms of the extent of drug absorption. However, in the Committee for Proprietory Medicinal Products (CPMP) guideline for the investigation of bioavailability and bioequivalence, the former is defined as the rate and extent to which the active substance of therapeutic moiety is absorbed from a pharmaceutical form and becomes available at the site of action. The reason that bioavailability has been defined in this way is because rate, as well as extent, is important when comparing the bioavailability of two pharmaceutical forms of an active substance to determine whether they are bioequivalent. Bioequivalence and comparative bioavaUabUity are discussed later but absolute bioavailabihty will be described first. 

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