Bioequivalence Study of Two Terazosin Formulations : $TZC^{\circledR}Tablet$ and $Hytrin^{\circledR}Tablet$

Terazosin 제제인 티지씨$^{\circledR}$정의 하이트린$^{\circledR}$정에 대한 생물학적동등성 시험

Background : Terazosin is an ${\alpha}-adrenergic$ receptor blocker and is used for the treatment of mild to moderate hypertension and benign prostatic hyperplasia. Terazosin can be administered once daily because of its high oral bioavailability of about 90% and long half-life of 9 to 12 hours. $TZC^{\circledR}tablet$ is an oral terazosin formulation that was intended to be developed as a generic formulation of $Hytrin^{\circledR}tablet$, an existing oral terazosin formulation in Korea. Therefore, we compared the pharmacokinetic characteristics and tested the bioequivalence of the two formulations in healthy Korean male subjects. Methods: The study was conducted as an open-labeled, randomized, 2-way crossover Latin square design in 18 healthy subjects. Subjects were separated into two groups. Subjects in one group were planned to be administered single doses of $Hytrin^{\circledR}tablets$ orally and one week later single doses of $TZC^{\circledR}tablets$. Subjects in another group were planned to be administered in opposite sequence in the same manner. Originally drugs in each period were to be administered in two divided days to 9 subjects each day, to guarantee the safety and well-being of subjects. But, actually, subjects were administered in three divided days to 7, 7 and 4 subjects respectively, due to private reasons of some subjects. Dosage administered was 1 mg as terazosin. Serial blood samples were collected till 48 hours after the drug administration. Plasma terazosin concentration were assayed by reversed phase HPLC using prazosin as internal standard. Pharmacokinetic parameters of the two formulations were analyzed by noncompartmental methods. We tested the sequence effect, period effect and differences of parameters between the two formulations by ANOVA. The pharmacokinetic characteristics of the two parameters were compared by 90% confidence intervals for ratios of $AUC_{0-{\infty}}$ and Cmax and the other pharmacokinetic parameters by student t-tests. Result : There was no difference in date groups when we analyzed the effect of dispersion of dates of drug administration to subjects using ANOVA, for p value was 0.1209. There were no differences between sequence, period and treatment groups, too. Total AUC of $TZC^{\circledR}tablets$ was $278.74{\pm}79.28\;ng\;{\times}\;hr/ml\;(mean{\pm}SD)$, and that of Hytrin tablet was $276.57{\pm}83.79$. $C_{max}$ of $TZC^{\circledR}tablets$ was $26.61{\pm}7.16\;ng/ml\;(mean{\pm}SD)$, and that of $Hytrin^{\circledR}tablet$ was $26.54{\pm}8.46$. AUC ratio between two formulations in individual subjects was $1.019{\pm}0.138.\;t_{1/2}(terminal\;half-life)$, $T_{max}$(time to maximum concentration), MRT(mean residence time) were similar between two formulations. The 90% confidence interval of total AUC difference between two $formulations(-17.86{\sim}22.20)$ was within the 20% of AUC of $Hytrin^{\circledR}tablet$, a $reference(-55.31{\sim}+51.31)$. The 90% confidence interval of $C_{max}$ difference between two $formulations(-2.44{\sim}2.66)$ was also within the 20% of $C_{max}$ of $Hytrin^{\circledR}tablet(-5.31{\sim}+5.31)$. Therefore, $TZC^{\circledR}tablets$ and $Hytrin^{\circledR}tablet$ were bioequivalent. Conclusion : Bioequivalence study is a clinical trial with human beings as subjects. Therefore, we should conduct clinical trial with due regard to the safety and well-being of subjects. The dispersion of administration dates is likely to occur in actual clinical trial field. There were no statistically significant differences in date groups when analyzed by ANOVA test, and we could conclude that the administration of drugs in three divided days had no effect on the bioequivalence test results of the two formulations. In crossover test, the dispersion of administration dates does not matter because the crossover design structure itself exclude the intersubject variability. Also, the dispersion of administration dates would increase the possibility of concluding that two formulations are not bioequivalent although actually bioequivalent but it is not possible to conclude that two bioequivalent formulations are not bioequivalent. In this study, we concluded that $Hytrin^{\circledR}tablet$ and $TZC^{\circledR}tablets$ are bioequivalent although the dates of administration were dispersed to three days, for the dispersion of dates proved not to affect the bioequivalence test result of two formulations.