Labopharm Inc, Laval, Quebec, Canada.
J Clin Pharmacol. 2010 Dec;50(12):1438-49. doi: 10.1177/0091270009360979. Epub 2010 Feb 19.
An extended-release trazodone HCl formulation, Trazodone Contramid OAD (TzCOAD), was developed as scored 150-mg and 300-mg caplets for once-daily administration. Dose proportionality of intact and bisected caplets (dose range, 75-375 mg) was evaluated in a single-dose, randomized, 5-way crossover study. Plasma trazodone and m-chlorophenylpiperazine (mCPP) levels were determined using a validated liquid chromatography-tandem mass spectroscopy method. Dose proportionality was assessed based on confidence intervals for logarithmically transformed, dose-normalized maximum plasma concentration (C(max)), area under the plasma concentration versus time data pairs (AUC(0-t)), and area under the curve from time 0 to infinity (AUC(0-∞)) in relation to the acceptance range of 80% to 125% (bioequivalence approach). The power method, combined with confidence interval criteria, was also used to assess proportionality. The conclusion of dose proportionality was generally supported using the bioequivalence approach. Based on the power model, values of the slope and corresponding 90% confidence interval for trazodone C(max), AUC(0-t), and AUC(0-∞) were 0.948 (0.899-0.997), 0.920 (0.875-0.964), and 0.913 (0.867-0.958), respectively. All were within the acceptance interval (0.861-1.139). Results for mCPP also fell within the acceptance interval. TzCOAD exhibits linear pharmacokinetics over doses ranging from 75 to 375 mg and maintains its controlled-release properties when the caplets are bisected along the score line.
一种盐酸曲唑酮的延长释放制剂——曲唑酮控释片（Trazodone Contramid OAD，TzCOAD），被开发为可每日服用一次的 150mg 和 300mg 刻痕胶囊。在一项单次、随机、五交叉研究中，评估了完整和对半切开胶囊（剂量范围 75-375mg）的剂量比例关系。采用经验证的液相色谱-串联质谱法测定曲唑酮和 m-氯苯基哌嗪（mCPP）的血浆水平。基于对数转换后、剂量归一化的最大血浆浓度（C(max)）、血浆浓度与时间数据对（AUC(0-t)）和从 0 到无穷大的曲线下面积（AUC(0-∞)）的置信区间，评估了剂量比例关系，范围为 80%至 125%（生物等效性方法）。还使用了幂法结合置信区间标准来评估比例关系。生物等效性方法一般支持剂量比例关系的结论。基于幂模型，曲唑酮 C(max)、AUC(0-t)和 AUC(0-∞)的斜率和相应的 90%置信区间值分别为 0.948（0.899-0.997）、0.920（0.875-0.964）和 0.913（0.867-0.958），均在可接受范围内（0.861-1.139）。mCPP 的结果也在可接受范围内。TzCOAD 在 75 至 375mg 剂量范围内表现出线性药代动力学特性，并且当胶囊沿刻痕线对半切开时，仍保持其控释特性。
