| Summary: | 碩士 === 臺北醫學大學 === 藥學研究所 === 98 === Bioequivalence (BE) study plays an important role on the approval of generic drugs and has been discussed on national and international for more than thirty years. To establish BE between generic and brand-name drug, appropriate study design and analytical method are needed. Thus, the guidelines of U.S. FDA (2003) and EMEA (2010) recommend relevant study design and statistical method of bioequivalence study for industry. Losartan, a selective angiotensin II receptor blocker approved for treatment of hypertension which has active metabolite, losartan acid is the tenth among top 10 drug expenditure in Taiwan in 2009 and ten BE studies of generic drug for losartan are approved from 2001 to 2009 by T-FDA. Howerer, some physicians and patients have concern that generic and brand-name drugs may not be equivalent. Thus, the purpose of this study is to evaluate the BE study design of losartan in Taiwan as well as to investigate the pharmacokinetics (PK) of losartan in Taiwanese.
The method was to review the BE study reports of losaran in T-FDA to May, 2009, including analytical method, PK parameters, the statistical results of BE study and compare the PK parameters of reference drug within each case. Moreover, PK parameters obtained from 50 mg losartan of reference drug were compared with the literatures of different countries.
Finally, a total of 11 losartan BE reports (case 1-11) were included in this study. Nine cases (82%) of losartan BE studies were approved. The subject sample size and the clinical procedure in all cases were conformed to guideline. The choice of analyte was not unity. Among the reports of 50 mg losartan and losartan acid, the PK parameters showed no difference except half-life. In case 8, the half-life of losartan was significantly higher than the others (p<0.001) and in case 2 losartan acid was significantly lower than the others (p<0.05). There were no significantly difference of the PK parameters of losartan between the HPLC group and the LC-MSMS group but the half-life of losartan acid was significantly higher on LC-MSMS group (p<0.001). ln(Cmax) in all these losartan BE studies had high intra-subject coefficient of variation (>30%).
The results of pharmacokinetics of losartan in Taiwan in the 246 healthy adult male were shown below: AUC0→∞ was 477.92 ± 173.80 ng/ml‧h, Cmax was 269.65 ± 147.73 ng/ml, Tmax was 1.32 ± 0.80h and T1/2 was 2.30 ± 0.83 h. The data shows high variability and abnormal distribution of AUC even through log transformation. In the 120 healthy adult male, the AUC0→∞ of losartan acid was 3252.50 ± 800.17 ng/ml‧h, Cmax was 453.75 ± 131.73 ng/ml, Tmax was 3.49 ± 1.11 h and T1/2 was 4.99 ± 0.99 h. The data of losatan acid shows normal distribution of Cmax and AUC. Comparing to the published literature of losartan and losartan acid in other population, Cmax of losartan was significantly higher than that of Brazil (p<0.05) and Turkey (p<0.01), and also AUC of losartan was significantly higher than that of Brazil (p<0.001 ) and Turkey (p<0.01). Cmax and AUC of losartan acid in the present study was significantly higher than that of American (p<0.001), Finland (p<0.001), Brazil (p<0.001), Turkey (p<0.001) and Jordan (p<0.001).
According to the present review, the practice of losartan BE studies designs and results in these 11 cases seems to be well. The analytical methods using HPLC or LC-MSMS may not lead to the bias on predicting PK parameters of losartan and losartan acid. Base on BE study guidance, parent drug, losartan is a more suitable to evaluate BE statistical results. Besides this, further discussion is needed to assess that losartan belongs to a highly variable drug or not. From the result of pharmacokinetic parameters of losartan and losartan acid in this study, there may be higher metabolism of losartan to losartan acid in Taiwan residents than in Western.
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