Bioequivalence models

J. Vuorinem and J. Turunen, A three step procedure for assessing bioequivalence in the general mixed model framework, Stat. Med., 15, 2635 (1996). 

Kararli, T. T., Comparative models for studying absorption, A APS Workshop on Permeability Definitions and Regulatory Standards for Bioequivalence, Arlington, Aug. 17-19, 1998. 

Dressman JB and Yamada K (1991) Animal Models for Oral Absorption. In PG Welling, FLS Tse, SV Dinghe (Eds.), Pharmaceutical Bioequivalence, VI48. New York, Dekker, pp 727-739. 

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... 

Another collateral effect of the DESI project was the development of the abbreviated NDA, by which a generic version of the innovator product could satisfy the statutory preconditions for entering the market, without repeating the preclinical and clinical studies of the innovator. This administrative creation, designed to assure that generics were both pharmaceutically equivalent and bioequivalent to the pioneer product, was endorsed by Congress in 1984. As will be seen, this development had a staggering impact on the business model of the pharma industry. 

Model Bioequivalence Data Summary Tables E-Submission PDF Word Processed e.g., MS Word... 

R., Hauck, W.W. et al., An individual bioequivalence criterion regnlatory considerations, Stat. Med. 19, 2821-2842, 2000 Meyer, M.C., United States Food and Drug Administration requirements for approval of generic drug products, J. Clin. Psychiatry 62 (Suppl. 5), 4-9, 2001 Temple, R., Policy developments in regulatory approval, Stat. Med. 21, 2939-3048, 2002 Gould, A.L, Substantial evidence of effect, J. Biopharm. Stat. 12, 53-77, 2002 Chen, M.L., Panhard, X., and Mentre, F, Evaluation by simulation of tests based on nonlinear mixed-effects models in pharmacokinetic interaction and bioequivalence cross-over clinical trials, Stat. Med. 24,1509-1524,2005 Bolton, S., Bioequivalence studies for levothy-roxine, AAPS J. 7, E47-E53, 2005. 

An important limitation of compartment analysis is that it cannot be applied universally to any drug. A simpler approach that is useful in the case of bioequivalency testing is the model independent method. It is based on statistical-moment theory. This approach uses the mean residence time (MRT) as a measure of a statistical half-life of the drug in the body. The MRT can be calculated by dividing the area under the first-moment curve (AUMC) by the area under the plasma curve (AUC). ... 

Pentikis, H.S. Henderson, J.D. Tran, N.L. Ludden, T.M. Bioequivalence individual and population compartmental modeling compared to the non-compartmental approach. Pharm. Res. 1996, 75, 1116-1121. 

Hu, C. Moore, K.H. Kim, Y.H. Sale, M.E. Statistical issues in a modeling approach to assessing bioequivalence or PK similarity with presence of sparsely sampled subjects. J. Pharmacokinet Pharmacodyn 2004, 31 (4), 321-339. 

Dressman JB, Yamada K. 1991. Animal models for oral drug absorption. In Pharmaceutical Bioequivalence, ed. P Welling, FL Welling, pp. 235-66. New York Dekker... 

WHO (2006) Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms. Technical Report Series, No. 937,... 

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