Biogen Idec, Inc, Building 6A-2, 14 Cambridge Center, Cambridge, MA 02142, USA.
J Clin Pharmacol. 2011 Jul;51(7):1004-14. doi: 10.1177/0091270010377633. Epub 2010 Oct 6.
Tonapofylline is an antagonist of adenosine A1 receptor being developed for heart failure. In the present studies, pharmacokinetic characteristics, including dose proportionality, bioavailability, and effects of gender and food, were evaluated in healthy subjects receiving single-dose tonapofylline (0.2-375 mg) in a parallel or crossover design. Following oral administration, tonapofylline concentrations mostly peaked within 3 hours and declined over time in a multiple phasic manner. Based on a power model, dose proportionality of peak concentration (C(max)), area under the time-concentration curve for all values (AUC(all)), and area under the time-concentration curve to infinity (AUC(inf)) was concluded in a clinical setting. The bioavailability of tonapofylline was 81.2% (90% confidence interval, 70.6%-93.5%). Following intravenous administration, the steady-state volume of distribution of tonapofylline was estimated to be 756 mL/kg. The total clearance of tonapofylline was low (64.8 mL/h/kg), approximately 5% of hepatic blood flow. The terminal half-life was variable within groups and ranged from 11.2 to 24.2 hours across the dose range. Female subjects showed significantly higher C(max), AUC(all), and AUC(inf) than male subjects (P < .05). Food decreased C(max) by approximately 39%, whereas it did not appear to affect AUC(all) and AUC(inf). The intersubject variability of the pharmacokinetic parameters of tonapofylline was generally less than 30%. In these studies, a single dose of tonapofylline was safe and well tolerated.
茶碱尼是一种腺苷 A1 受体拮抗剂，目前正在开发用于心力衰竭。在这些研究中，采用平行或交叉设计，在健康受试者中单次给予茶碱尼（0.2-375mg），评估了药代动力学特征，包括剂量比例性、生物利用度以及性别和食物的影响。口服后，茶碱尼浓度大多在 3 小时内达到峰值，并以多相方式随时间下降。基于幂模型，得出了临床环境中峰浓度（C(max)）、所有时间浓度曲线下面积（AUC(all)）和时间浓度曲线下无穷大面积（AUC(inf)）的剂量比例性。茶碱尼的生物利用度为 81.2%（90%置信区间，70.6%-93.5%）。静脉给药后，茶碱尼的稳态分布容积估计为 756mL/kg。茶碱尼的总清除率较低（64.8mL/h/kg），约为肝血流量的 5%。终末半衰期在组内变化，在整个剂量范围内为 11.2-24.2 小时。女性受试者的 C(max)、AUC(all)和 AUC(inf)明显高于男性受试者（P<0.05）。食物使 C(max)降低约 39%，但似乎不影响 AUC(all)和 AUC(inf)。茶碱尼药代动力学参数的个体间变异性通常小于 30%。在这些研究中，单次给予茶碱尼是安全且耐受良好的。
