Bioequivalency measurement

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). 

Proponents of the clinical mirror theory of bioequivalence would like to see increased emphasis placed on quantification of pharmacodynamic values. In some instance we can readily identify how reliable and relevant pharmacodynamic values can be measured. For example, for an antihypertensive drug, measurement of blood pressure changes can be conveniently, inexpensively and objectively determined. However, for other types of drug (e.g., antidepressants) it is not easy to conceive any simple pharmacodynamic attributes that could be readily determined. 

Even the most superficial evaluation of bioequivalency requirements for controlled-release products will indicate that for some of these products, at least, the conventional AUC, Tmax, and Cmax measures of bioequivalency may well be insufficient. Thus, for a non-pulsatile sustained-release product with a dosing interval of 24 hours (as compared to 4 hours for the noncontrolled product), the time period during which plasma concentrations are maintained at essentially a plateau level might well be regarded as of critical... 

Obviously, if the clinical mirror approach to bioequivalency testing gains momentum, we may expect to see more quantification of clinical response in bioequivalency studies. In some instances pharmacodynamic parameters that are amenable to precise quantification are easily identified. Thus, if we are working with an antihypertensive drug, measurement of blood pressure using an electronic sphygnomanometer is an obvious option. However, for many drugs there is no simple way to quantify pharmacodynamic response. In some cases we may have to rely, to some extent at least, on patient diaries [41]. Such techniques are open to criticism of subjectivity and imprecision. 

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. 

Over the last quarter century the dissolution test has emerged as a most powerful and valuable tool to guide formulation development, monitor the manufacturing process, assess product quality, and in some cases to predict in vivo performance of solid oral dosage forms. Under certain conditions, the dissolution test can be used as a surrogate measure for bioequivalence (BE) and to provide biowaivers, assuring BE of the product. Dissolution test has turned out to be a... 

Note that a choice of pH 6.8 test conditions for quality control assures that at least one of these three criteria will be met by the product, thus harmonizing quality control measures with biopharmaceutical tests for bioequivalence. 

How the baseline measurement will be used in relation to the critical evaluable endpoints must be determined before analysis. Comparison of two or more treatments usually takes into account the differences between baseline values between treatment groups at the point of randomisation. The way in which the analysis will influence the report and publications needs to be decided, as some regulatory authorities have their own statistical criteria that need to be observed (e.g. for bioequivalence studies ). 

Bioequivalence (e.g. equivalence of efficacy) of two different galenical formulations of the same compound as measured by maintained remission rates in schizophrenic patients after an oral or depot antipsychotic formulation. 

Measurement of Metabolites. The elimination of drug usually happens through metabolites that are more polar than the drug itself to enhance their excretion via urine or bile. Some special situations exist in bioavailability/bioequivalence that require the determination of metabolites ... 

Stereoisomer Assays. There are many drugs that are administered as racemic mixtures. They may undergo stereoselective metabolism and/or elimination, and one isomer may be more active than the other. Therefore, there is the need to develop and validate bioanalytical assays for stereoselective determination in bioavailability/bioequivalence studies. All methods used for measurement of stereoisomer should be validated (with emphasis on stereospecificity). For bioequivalence studies of an existing racemic product, a stereospecific assay is not required if the rate and extent of profiles are superimposable (within the usual statistical boundaries) [3,23]. 

Morris, D.H. 2003b. Methodologic challenges in designing clinical studies to measure differences in the bioequivalence of n-3 fatty acids. Mol. Cell. Biochem. 246, 83-90. 

Pivotal Bioequivalence Studies General recommendations for a standard BE study based on pharmacokinetic measurements are provided in Attachment A. 

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