Criteria to Assess In Vivo Performance and Bioequivalence of Generic Controlled‐Release Formulations of Carbamazepine
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Summary: Purpose: Concern persists that the criteria used to establish bioequivalence of generic drugs may not adequately guarantee the interchangeability of antiepileptic medications (AEDs), particularly controlled‐release (CR) formulations. We examined the utilization of several new parameters, in addition to AUC, peak plasma concentration (C max ), and time to reach C max (t max ), for the assessment of bioequivalence and in vivo performance of CBZ and other CR products. These new parameters may offer additional information for evaluation of CR products that yield a prominent plateau in the plasma time‐concentration curve. They include mean residence time (MRT), C max /AUC, plateau time or POT (the time span associated with the concentrations within 25% of C max ), t apical , and C apical , (the arithmetic mean of the POT times and concentrations within 25% of C max respectively). Additional parameters for multiple‐dose studies include the percentage fluctuation and the flatness of the steady state‐concentration curve. Methods: These proposed parameters were used in two recent (single and multiple dose) two‐way crossover studies of a new CR product of CBZ (Teril 400 CR) in comparison with Tegretol CR Divitab. Results: Teril 400 CR was found to be bioequivalent to Tegretol CR Divitab, by using both the classic and the additional proposed parameters. Both CBZ CR products have similar rates of absorption and similar flatness of their plasma time‐concentration curves as assessed by visual inspection and the proposed parameters. Conclusions: The additional parameters examined may supplement the traditional single‐point parameters, C max and t max for assessment of rate of absorption and the flatness of the concentration curve. Their potential benefit and practical utility was confirmed in these two studies. Absorption‐rate assessment is important in light of concentration‐related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ plasma concentration curve on the drug efficacy and tolerability.Keywords:
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To monitor the performance of the approved generic copies of a brand-name drug, we propose some methods in assessing bioequivalence among generic copies and the brand-name drug, and among generic copies themselves, using data from several bioequivalence studies adopting the standard 2 x 2 crossover design without carryover effects. We propose a meta-analysis method that increases statistical power when the between-subject variability is not large. A nonmeta-analysis is also considered. A numerical example of applying both methods is presented for illustration.
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The introduction of generic medicines brings about the debate around drug efficacy and safety, where bioavailability and bioequivalence play an important role. In recent years, many questions have emerged regarding utilisation of average bioequivalence as the only criterion of evaluating bioequivalence for all drug categories. In this scenario, population and individual bioequivalence were presented as alternative criteria. This paper aims to discuss some of the main questions concerning average bioequivalence as criterion of evaluating bioequivalence, especially in the interchangeability aspect, and emphasises the main differences among these three methodologies: average, population and individual bioequivalence.
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Considering that a study of bioequivalence is not compulsory for drug registration in many Latin-American countries, a trial using a bioequivalent preparation of enrofloxacin (bENR) and a non-bioequivalent one (nbENR) was carried out in broilers to assess the maximum serum concentrations (Cmax) and area under the plasma drug-concentration vs. time profiles (AUC) obtained. Three levels of drug handling when delivering the medicated water to the birds have been identified in poultry producing units in Mexico i.e., poor, medium and high. The trial was carried out in eight thousand, divided in six groups with three replicates per group. Variables included in handing the medicated water were grouped to integrate the poor, medium and high groups. The highest AUC and Cmax values were obtained with the bENR handled under high standards (P<0.05). The nbENR, similarly handled, failed to achieve adequate values in these variables. Medium and poor drug management either with bENR or nbENR resulted in low to very low Cmax and AUC values, reaching a lowest value of Cmax of 0.17μg/mL, equivalent to 7% of the best Cmax (2.43μg/mL). It is concluded that excepting in the bENR handled with high standards, all groups showed insufficient Cmax/MIC and AUC/MIC ratios. Relevance of these findings for clinical efficacy and for the emergence of bacterial resistant strains is discussed.
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The problem of drug interchangeability among a brand-name drug and its generic copies is considered. Under current Food and Drug Administration (FDA) regulation, a patient may switch from the brand-name drug to a generic drug if the generic drug is shown to be bioequivalent to the brand-name drug based on bioequivalence testing. After the patent of a brand-name drug is expired, usually there will be a number of generic copies available on the market. The FDA does not indicate that a patient may switch from a generic to another even though both of the generic drugs are bioequivalent to the brand-name drug. As a result, drug interchangeability among the brand-name and its generic copies is a safety concern. In this paper, we propose to perform a meta-analysis for an overview of bioequivalence. The proposed meta-analysis provides an assessment of bioequivalence among generic copies of a brand-name that can be used as a tool to monitor the performance of the approved generic copies of the brand-name drug. In addition, it provides more accurate estimates of inter- and intrasubject variabilities of the drug product.
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The study is to conduct the Bioequivalence study of an
Antidepressant, in accordance with the regulatory authority. The BE study is conducted
on a test product, ‘T’and reference product ‘R’. ‘T’, and ‘R’are oral Tablet containing
drug Cinitapride. In a dose of 150mg. Drug Cinitapride is an Gastrointestinal motility
treatment drug.
The study objectives included: Assessment of the bioavailability of test product A while comparing with a
reference product B in 6 normal, adult, human subjects under fasting
condition. The bioequivalence assessed is to be assessed under following
pharmacokinetic Parameters: AUC0-t, AUC0-∞, Cmax, Tmax, Kel, and t1/2. Monitoring of the adverse events and ensure safety of the subjects. Bioequivalence is evaluated by three pharmacokinetic parameters viz., AUC,
Cmax and Tmax out of which AUC and Cmax are main parameter for evaluation.
The pharmacokinetic parameters (AUC and Cmax) of Cinitapride are within the
acceptable limits of bioequivalence 80% - 125%.
Hence, it is concluded that single dose bioequivalence study of Cinitapride 3 mg
tablet (each containing Cinitapride 3 mg) is bioequivalent with Cintpro 3 mg tablet
(each containing Cinitapride 3 mg)
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As more and more generics become available in the market place, the safety/efficacy concerns may arise as the result of interchangeably use of approved generics. However, bioequivalence assessment for regulatory approval among generics of the innovative drug product is not required. In practice, approved generics are often used interchangeably without any mechanism of safety monitoring. In this article, based on indirect comparisons, we proposed several methods to assessing bioequivalence and interchangeability between generics. The applicability of the methods and the similarity assumptions were discussed, as well as the inappropriateness of directly adopting adjusted indirect comparison to the field of generics' comparison. Besides, some extensions were given to take into consideration the important topics in clinical trials for bioequivalence assessments, for example, multiple comparisons and simultaneously testing bioequivalence among three generics. Extensive simulation studies were conducted to investigate the performances of the proposed methods. The studies of malaria generics and HIV/AIDS generics prequalified by the WHO were used as real examples to demonstrate the use of the methods. Copyright © 2017 John Wiley & Sons, Ltd.
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For immediate release drug formulations the maximum concentration (Cmax), the time to the maximum concentration (tmax), and the ratio Cmax/AUC have been suggested as absorption rate characteristics. Although tmax is easier to interpret as absorption rate characteristic than Cmax and Cmax/AUC, the latter are generally preferred in practice because these characteristics can be observed with higher precision, and are easier to handle statistically than tmax. In this paper we propose a strategy for setting appropriate bioequivalence ranges for tmax and Cmax/AUC, and for choosing the best characteristic for the comparison of absorption rates when planning a bioequivalence study. This involves motivating the bioequivalence range on that scale which is most convenient for that purpose, namely in terms of differences in tmax. Exploiting the pharmacokinetic relationship between tmax and Cmax/AUC this bioequivalence range is then translated into the corresponding bioequivalence range for Cmax/AUC. The characteristic that gives the greatest power to show bioequivalence can then be specified as the primary absorption rate characteristic. For drugs with short elimination half-lives, or short fastest disposition half-lives if the drug concentrations follow a higher compartmental model, Cmax/AUC is the best characteristic, but for drugs with long elimination or fastest disposition half-lives tmax can be superior to Cmax/AUC.
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