Bioequivalence limitations

The Chinchilli metric (24,27), defined as the ratio of the test region area over the reference region area, uses a reference region area specified by i L = 0.8i and Ru = 1.2R as upper/lower acceptance (bioequivalence) limits for the reference. This is compared with the test region area mentioned earlier. The procedure as such appears rather complicated. 

Tothfalusi, L., Endrenyi, L., and Midha, K., Scaling or wider bioequivalence limits for highly variable drugs and for the special case of C(max), International Journal of Clinical Pharmacology and Therapeutics, Vol. 41, No. 5, 2003, pp. 217-225. 

Karalis, V., Symillides, M., and Macheras, P., Novel scaled average bioequivalence limits based on GMR and variability considerations, Pharmaceutical Research, Vol. 21, No. 10, 2004, pp. 1933-1942. 

In vitro dissolution of new formulations slow and fast within the bioequivalence limits... 

In general the acceptance limit 0.80-1.25 should be applied to the Cmax-ratio. However, this measure of relative bioavailability is inherently more variable than, for example, the AUC-ratio, and in certain cases a wider acceptance range (e.g. 0.75-1.33) may be acceptable. The range used must be defined prospectively and should be justified, taking into account safety and efficacy considerations. In exceptional cases, a simple requirement for the point estimate to fall within bioequivalence limits of 0.80-1.25 may be acceptable with appropriate justification in terms of safety and efficacy. 

Karalis V, Macheras P, Symillides M. Geometric Mean Ratio-dependent scaled bioequivalence limits with leveling-off properties. Eur J Pharm Sci 2005 26 54-61. 

Both bioavailability and bioequivalence focus on measuring the absorption of the drug into systemic circulation hence, similar study design approaches are used to establish bioavailability of a drug or to assess bioequivalence. Bioavailability is a comparison of the drug product to an intravenous formulation, a solution, or a suspension, whereas bioequivalence is a more formal comparative test that uses specified criteria for comparisons with predetermined bioequivalence limits for evaluation. 

In the past 20 years the evaluation criteria for bioequivalence studies recommended by the FDA have evolved and been revised several times. For bioequivalence comparisons the new formulation or method of manufacture is the test product (7) and the prior formulation or method of manufacture is the reference (R) product. To establish bioequivalence, the difference between the bioavailability of the test product and the reference product must be within the prespecified bioequivalence limit as governed by the approach taken to assess bioequivalence, which is discussed in this section. 

The current evaluation criteria are based on the two one-sided test approach, also commonly referred to as the Confidence Interval Approach or Average Bioequivalence, which determines whether the average values for the pharmacokinetic parameters measured after the administration of test and reference products are comparable. This approach involves the calculation of a 90% confidence interval about the ratio of the averages of T and R products for AUC and values. To establish bioequivalence, the AUC and of the T product should not be less than 0.80 (80%) or greater than 1.25 (125%) of the R product based on log-transformed data (i.e., a bioequivalence limit of 80 to 125%). For some time prior to the use of log-transformed data, the nontransformed data were used to assess bioequivalence. In 1989, it was realized that log transformation of the data enables a comparison based on the ratio of the two averages rather than the difference between the averages in an additive manner." Moreover, most biological data correspond to a log-normal distribution rather than to a normal distribution. 

There are special problems in bioequivalency determinations when conventional pharmacokinetic studies are not possible. For example, when drugs are administered intranasally for direct treatment of receptors in the nasal mucosa, the concentration of drug in plasma may be below the limit of quantification. In such cases we are forced to attempt measurement of clinical response. The subjectivity and/or low precision of this type of study can be a serious problem. 

C. T. Rhodes, Acceptable limits in bioequivalence studies, Clin., Res. Drug Reg. Affaris, 14, 127 (1997). 

I. Mohmood and H. Mahayni, A limited sampling approach in bioequivalence studies application to long half life drugs and replicate design studies, Int. J. Clin. Ther, 37, 275 (1999). 

H. C. Hsu and H. L. Lu, On confidence limits associated with Chow and Shao s joint confidence region approach for assessment of bioequivalence, J. Biopharm Stat., 7, 125 (1997). 

Other applications include bioequivalent measurements of bromazepam, an anticonvulsant, in human plasma. The lower limit of quantitation (LLOQ) was 1 ng/mL (Gongalves et al. 2005). Kuhlenbeck et al. (2005) studied antitussive agents (dextromethorphan, dextrophan, and guaifenesin) in human plasma LLOQ values were 0.05, 0.05, and 5 ng/mL, respectively. Other compounds studied were nucleoside reverse transcriptase inhibitors, zidovudine (AZT) and lamivudine (3TC) (de Cassia et al. 2004) and stavudine (Raices et al. 2003) in human plasma, and paclitaxel, an anticancer agent, in human serum (Schellen et al. 2000). 

In general, bioequivalence is demonstrated if the mean difference between two products is within 20% at the 95% confidence level. This is a statistical requirement, which may require a large number of samples (e.g. volunteers), if the drug exhibits variable absorption and disposition pharmacokinetics. For drugs for which there is a small therapeutic window or low therapeutic index, the 20% limit may be reduced. The preferred test method is an in vivo crossover study and, since this occurs in the development phase, necessitates the emplo)unent of volim-teers. These studies are, therefore, expensive and animal experiments may be substituted, or in vitro experiments if they have been correlated with in vivo studies. 

Bioequivalence problems have been documented in the past for products marketed by different manufacturers however, studies in patients have shown comparable clinical efficacy between brands based on the results of thyroid function tests brand interchange should be limited to products with demonstrated therapeutic equivalence... 

Validation parameter Confirmation of the identity of pure substances Determination of identity of unknown substances Amount single pure substance Amount active substance Limit test (semi- quantitiative) Amount impurities/ degradation products (quantitative) Dissolution speed of substances Bioequivalence studies... 

Important specifications for the manufacture of all solutions include assay and microbial limits. Additional important specifications for suspensions include particle size of the suspended drug, viscosity, pH, and in some cases, dissolution. Viscosity can be important, from a processing aspect, to minimize segregation. In addition, viscosity has also been shown to be associated with bioequivalency. pH may also have some meaning regarding effectiveness of preservative systems and may even have an effect on the amount of drug in solution. With regard to dissolution, there are at least three products that have dissolution specifications. These products include pheny-toin suspension, carbamazepine suspension, and sulfamethoxazole and trimethoprim suspension. Particle size is also important, and at this point it would seem that any... 

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