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      Metrics for the Evaluation of Bioequivalence of Modified-Release Formulations

      , 1 , 2

      The AAPS Journal

      Springer US

      bioequivalence, metrics, modified release, steady state, therapeutic equivalence

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          Abstract

          Metrics are discussed which are used for the evaluation of bioequivalence of modified-release formulations. In order to ensure the therapeutic equivalence of the compared drug products, it would be important to contrast measures which are additional to area under the curve (AUC) and C max. For delayed-release products, the assessment of lag times is informative. For extended-release dosage forms, comparisons of the half-value duration and the midpoint duration time are useful. For some modified-release formulations with complicated, multiphasic concentration profiles, the comparison of partial AUCs is important. In determinations of the bioequivalence of extended-release dosage forms, investigations performed under steady-state conditions rather than after single dosing can yield enhanced probability of therapeutic equivalence, especially with substantial accumulation of the drug products. In steady-state investigations of bioequivalence, evaluation of the trough concentration and of the peak trough fluctuation is informative.

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          Most cited references 46

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          Methylphenidate bioavailability from two extended-release formulations.

          The objective of these studies was to compare the rate and extent of absorption of d,l-threo-methylphenidate (MPH) from two extended-release products--a capsule formulation containing coated beads and an OROS tablet formulation--in healthy male and female subjects under fasted conditions. Metadate CD (methylphenidate HCl, USP) Extended-Release Capsules and Concerta (methylphenidate hydrochloride) Extended-Release Tablets. Two studies were conducted: (1) A single dose, randomized, two-way crossover study in 36 adults comparing a 20 mg capsule and an 18 mg tablet, and (2) a single dose, randomized, four-way crossover study in 24 adults comparing 2 x 20 mg capsules, one 36 mg tablet, 3 x 20 mg capsules and one 54 mg tablet. Blood samples were collected over 24 hours and MPH plasma concentrations were used to calculate pharmacokinetic parameters for each treatment. Equivalence of pharmacokinetic parameters for comparable doses of the formulations was concluded if the 90% confidence intervals (CI) for the ratio between test and reference means were within the 80-125% equivalence criterion. Both formulations exhibited biphasic plasma concentration-time profiles and were equivalent in terms of total exposure (AUC(0-last) and AUC(0-infinity)). However, early exposure (AUC(0-4) and AUC(0-6), the first maximum measured plasma concentration (C(max-1), and early plasma MPH concentrations (1.5, 3 and 4 hours) were greater with the capsule formulation, while later plasma MPH concentrations (8, 10 and 12 hours) were greater with the tablet formulation (the CIs were outside the 80-125% required for equivalence and p < 0.001 for all). Similar results were obtained whether or not the data were normalized for the difference in total dose. The two formulations are not bioequivalent. The capsule fonnulation produces greater exposure to MPH and higher MPH concentrations during the first 6 hours following dosing. MPH is frequently used in school children, and this period would correspond to a major part of the school day.
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            Pharmaceutical quality of docetaxel generics versus originator drug product: a comparative analysis.

            The aim of this study was to evaluate the quality of 31 commercially available generic formulations of docetaxel purchased in 14 countries by comparing their docetaxel content, impurity levels and pH versus those of the proprietary product Taxotere (Tx). Generic formulations were purchased in 14 countries in Asia, Africa, the Middle East and Latin America. Levels of docetaxel and impurities (chromatographic peaks above 0.05%) were obtained for each sample using reverse-phase liquid chromatography with ultraviolet detection. The pH of aqueous solutions of generic docetaxel formulations and Tx was also measured. A global evaluation of quality was conducted on each product using a multicriteria desirability analysis based on standards defined by the International Conference on Harmonisation guidelines and the US Pharmacopeia paclitaxel injection monograph. Most generic formulations contained a lower than expected amount of docetaxel and/or a high level of impurities: 21 generic docetaxel formulations had an average mass of docetaxel that was 3.0%, almost twice the level of impurities in Tx 20 mg. In total, 33 impurities not present in Tx were detected in the generic samples. Desirability analysis demonstrated that none of the generic docetaxel formulations had composition characteristics similar to those of Tx. This study demonstrated that from an analytical point of view, 90% of the generic docetaxel formulations evaluated contained insufficient active drug, high levels of impurities or both. This has the potential to affect both efficacy and safety of the drug.
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              Measures of exposure versus measures of rate and extent of absorption.

              Regulatory assessment of bioavailability and bioequivalence in the US frequently relies on measures of rate and extent of absorption. Rate of absorption is not only difficult to measure but also bears little clinical relevance. This paper proposes that measures of bioavailability and bioequivalence for drugs that achieve their therapeutic effects after entry into the systemic circulation are best expressed in terms of early [partial area under the concentration-time curve (AUC)], peak plasma or serum drug concentration and total AUC exposure for a plasma or serum concentration-time profile. With suitable documentation, these systemic exposure measures can be related to efficacy and tolerability outcomes. The early measure is recommended for an immediate release drug product where a better control of drug absorption is needed, for example to ensure rapid onset of a therapeutic effect or to avoid an adverse reaction from a fast input rate. The 3 systemic exposure measures for bioavailability and bioequivalence studies can provide critical links between product quality and clinical outcome and thereby reduce the current emphasis on rate of absorption.
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                Author and article information

                Contributors
                +1-416-9253779 , +1-416-9786395 , l.endrenyi@utoronto.ca
                Journal
                AAPS J
                AAPS J
                The AAPS Journal
                Springer US (Boston )
                1550-7416
                22 August 2012
                22 August 2012
                December 2012
                : 14
                : 4
                : 813-819
                Affiliations
                [1 ]Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8 Canada
                [2 ]Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary
                Author notes

                Guest Editors: James Polli, Jack Cook, Barbara Davit, and Paul Dickinson

                Article
                9396
                10.1208/s12248-012-9396-8
                3475860
                22910857
                © The Author(s) 2012
                Categories
                Review Article
                Custom metadata
                © American Association of Pharmaceutical Scientists 2012

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