Bioequivalence assessment

M. L. Chen and A. J. Jackson, The role of metabolites in bioequivalency assessment, I. Linear pharmacokinetics without first pass effect, Pharm. Res, 8, 25 (1991). 

S. K. Niazi, S. M. Alam, and S. I. Ahmad, Patial area method in bioequivalence assessment naproxen, Biopharm Drug Dispos., 18, 103 (1997). 

Diltiazem Functional relationship between PK and PD parameters is described by hysteresis loops with a clockwise rotation. This cannot be explained in the classical way by the time lag between central and effect compartments. The model of down regulation/toler-ance development is proposed as a result supported by the finding that the shape of the hysteresis is dependent on the absorption rate of diltiazem, calculated as mean input time. Acute tolerance to dilitazem develops at least with the electrophysiologi-cal action of diltiazem after oral application and that the extent of tolerance development increases when decreasing its absorption rate. Bioequivalence assessment of diltiazem is possible using PD parameters however, because PK/PD relationships are influenced by the absorption rate, extent parameters may be misinterpreted when rate parameters of the test formulations are different... 

An underlying premise of bioequivalence assessments is a clearly defined phar-macokinetic/pharmacodynamic relationship however, the relation between blood levels and effect is less clearly established for proteins [20]. 

The mean concentration-time profiles for each of the four analytes, and for each of the two formulations, generated by this study are shown in Fig. 7. The pharmacokinetic comparisons derived from this study for all four analytes are summarized in Table 4. As can be seen from Fig. 7 and Table 4, a four-way bioequivalence assessment proved both feasible and practical. This study also demonstrated that si ar formulations will produce similar concentration-time profiles for all the enantiomers in the plasma (even given lot-to-lot variability, manufacturing site-to-site variability, and shelf-time variability). 

The fundamental assumption in bioequivalence assessment is that systemic clearance of the drug remains constant across phases of the study (crossover design) or between the animals used in the study (parallel-groups design). This follows from the equation... 

For further discussion of bioequivalence the reader should refer to review of the 1993 Veterinary Drug Bioequivalence Workshop (Martinez Riviere, 1994), the review paper Veterinary drug bioequivalence determination (Toutain Koritz, 1997) and the chapter entitled Bioavailability bioequivalence assessments (Martinez Berson, 1998) in Development and Formulation of Veterinary Dosage Forms, 2nd edn. 

Martinez, M.N. Berson, M.R. (1998) Bioavailability/bioequivalence assessments. In Development and Formulation of Veterinary Dosage Forms, (eds G.E. Hardee and J.D. Baggot), 2nd edn. pp. 429-467. Marcel Dekker, New York. 

Colburn WA. 1995. Clinical markers and endpoints in bioequivalence assessment . Drug Inf. J. 29 917. 

The primary concern in bioequivalence assessment is to limit the risk of a false declaration of equivalence. Statistical analysis of the bioequivalence trial should demonstrate that a clinically significant difference in bioavailability between the multisource product and the comparator product is unlikely. The statistical procedures should be specified in the protocol before the data collection starts. 

Veterinary Drug Availability, Basis for Selection 3 of the Dosage Form, Formulation of Veterinary Dosage Forms, Protein/Peptide Veterinary Formulations, Formulation of Vaccines, Administration Devices and Techniques, Specification Development and Stability Assessment, Bioavailability Bioequivalence Assessments, Development and Formulation of Dosage Forms, Design of Preclinical Studies... 

Wijnand, H.P. (1994) Bioequivalence assessment of drug formulations non-parametric versus parametric analysis. Ph.D. thesis. University of Leiden, Leiden,... 

Traditional bioequivalence assessment is based on a specific linear model with sequence and period effects (see Schuirmann (1)). Because the E aax curve is nonlinear, it is unclear as to how best to accommodate sequence and period effects. Given the desire of limiting study complexity, simplification in analysis method(s) is necessary to make them suitable in a potential regulatory setting. Thus, we will ignore period and sequence effects. We consider three potential methods to estimate the relative bioavailability F. 

Fluehler H, Hirtz J, Moser HA (1981) An aid to decision-making in bioequivalence assessment. Journal of Pharmacokinetics and Biopharmaceutics 9 223-243. 

Fluehler H, Grieve AP, Mandallaz D, Mau J, Moser HA (1983) Bayesian approach to bioequivalence assessment an example. Journal of Pharmaceutical Sciences 72 1178-1181. 

Hauschke D, Steinijans VW, DUetti E, Burke M (1992) Sample size determination for bioequivalence assessment using a multiplicative model. Journal of Pharmacokinetics and Biopharmaceutics 20 557 561. 

Hauschke D, Steinijans VW, Hothorn LA (1996) A note on Welch s approximate t-solution to bioequivalence assessment. Biometrika 83 236-237. 

Mandallaz D, Mau J (19 81) Comparison of different methods for decision-making in bioequivalence assessment. Biometrics 37 213-222. 

Bioequivalence assessments of drugs that are insignificantly absorbed into the systemic circulation are difficult. In some cases, for such drugs a biological marker has been established for the assessment of bioequivalence. Examples of biological markers used are skin blanching in the case of hydrocorticosteroids and neutralization of stomach acid for antacids. For certain cases a pharmacodynamic end point may be more appropriate for the assessment of bioequivalence. 

---