生物等效性和生物利用度杂志

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Effect of Truncated AUC Method on Drug Bioequivalence in Humans

Naji M. Najib, Isam Salem, Rana Hasan and Nasir M. Idkaidek

The purpose of this study is to investigate the eff ect of using truncated area under the curve AUC) method on the bioequivalence of different drugs in healthy volunt eers. Model drugs used clopidogrel, glimepiride, losartan , carvedilol, carbamazepine, diazepam, donepezil, tra madol and repaglinide. 24 – 38 healthy subjects participa ted in each study using cross over design. Individual disp osition kinetic parameters of areas under plasma concentrat ions (AUC 0-t , AUC 00 ), maximum concentration (C max ) and time to reach maximum concentration (T max ) were calculated by non-compartmental analysis using Kinetica progra m V 4.2 using all data points. In addition, truncated A UC was calculated up to median T max of reference product. No di- rect correlation was shown between study results du e to AUC truncation. The 90 % confidence intervals for l og- transformed AUC 0-t , AUC 00 , and C max were not always in agreement with the 90 % confidence intervals for lo g-trans- formed truncated AUC. More over, the 90 % confidenc e intervals for log-transformed AUC 0-t , AUC 00 passed in all drugs, while those for C max failed in 3 drugs and for trun- cated AUC failed in seven drugs. This indicates tha t C max , AUC 0-t , AUC 00 rather than truncated AUC are more accu- rate to determine formulation differences, which is the goal of bioequivalence studies. It was shown that intra- subject variability is usually higher in truncated AUC as c ompared to variabilities of AUC 0-t , AUC 00 , and Cmax. This rendered the sample size to be in adequate for calculation o f tuncated AUC parameter, which explained the high failure rat e in its limits. These results suggest not using truncat ed AUC to support the bioequivalence of drugs where rapid ab- sorption is of importance as recommended by the dra ft EMEA guideline.