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  • 1
    Electronic Resource
    Electronic Resource
    The Role of Metabolites in Bioequivalency Assessment. II. Drugs with Linear Pharmacokinetics and First-Pass Effect (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 700-708 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016259509257
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Bioequivalence of Methylphenidate Immediate-Release Tablets Using a Replicated Study Design to Characterize Intrasubject Variability (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 381-384 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007560500301
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    The Role of Metabolites in Bioequivalency Assessment. I. Linear Pharmacokinetics without First-Pass Effect (1991)
    Springer
    Pharmaceutical research 8 (1991), S. 25-32 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015865920043
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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