Bioequivalence of drugs

III. ROLES OF VARIOUS ENTITIES IN ASSURING BIOEQUIVALENCE OF DRUG PRODUCTS... 

L. Endrenyi and L. Tothfalusi, Truncated AUC evaluates effectively the bioequivalence of drugs with long half lives, Int. J. Clin. Phrmacol. Ther., 35, 42 (1997). 

Stippler E. Bioequivalent dissolution test methods to assess bioequivalence of drug products. Ph.D. dissertation, Johann Wolfgang Goethe University, Frankfurt am Main, 2004. 

Stippler E. Biorelevant Dissolution Test Methods to Asses Bioequivalence of Drug Products. Frankfurt Institute for Pharmaceutical Technology, J. W. Goethe University, 2004 414. 

Pharmacodynamic (PD) studies are also performed to estimate the bioavailability and bioequivalence of drugs from topically applied semisolids. In this case, known therapeutic responses from drug products such as skin blanching due to vasoconstrictor effects caused by corticosteroids and transepidermal water loss caused by retinoids are measured and compared between the test and reference... 

The measurement of the bioavailability and bioequivalence of drug dosage forms is commonplace. The numerous reasons for the increased use of such studies include rapid growth of the generic drug industry an increased awareness of the effect of dosage form on the rate and extent of drug absorption the development of more sensitive and reliable analytic methods to... 

The new millenium professional pharmacist with rigorous training in the scientific and clinical properties of drug substances and pharmaceutical formulations should be well able to dispassionately evaluate bioe-quivaleny data and give an objective, professional opinion as to validity of data purported to demonstrate generic bioequivalence. 

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. 

The United States Pharmacopeia (USP) (or other national or regional pharmacopeia) provides standards for a large number of drug substances and drug products. Some of these standards are particularly relevant to bioequivalency. First, USP products are... 

For development of bioequivalence studies (in which different formulations have been used in clinical trials), it would seem that normally there would be no need to conduct bioequivalency studies using a stereoselective assay for the evaluation of the concentrations of drug in the plasma samples. We would not usually expect any noticeable difference in the ratio of R to S isomer exiting in plasma samples derived at the same postdosing time point from different... 

Also, if conversion of drug to active metabolite shows significant departure from linear pharmacokinetics, it is possible that small differences in the rate of absorption of the parent drug (even within the 80-125% range for log transformed data) could result in clinically significant differences in the concentration/ time profiles for the active metabolite. When reliable data indicate that this situation may exist, a requirement of quantification of active metabolites in a bioequivalency study would seem to be fully justified. 

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. 

When pharmaceuticals are administered to feed animals there is a special concern about the possible accumulation of drug residues in the animals tissues. Thus, in these bioequivalency studies it may be appropriate to carefully monitor parameters that define possible tissue accumulation [45]. 

P. Sathe, J. Venitz, and L. Lesko, Evaluation of truncated areas in the assessment of bioequivalence of immediate release formulations of drugs with long half lives and CMax with different dissolution rates, Pharm. Res, 16, 939 (1999). 

Zemplar (paricalcitol) injection is a synthetically manufactured selective vitamin D receptor activator (SVDRA) indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD) stage 5. The U.S. Food Drug Administration (FDA) approved a capsule form of Zemplar for development to satisfy a need for an oral formulation. The objective of study M04-693 was to assess the bioequivalencies of several dosage strengths of paricalcitol capsules under fasting conditions. 

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