Contract Research Organization, Cadila Pharmaceuticals Ltd, Ahmedabad, Gujarat, India.
Am J Cardiovasc Drugs. 2010;10(2):95-103. doi: 10.2165/11532170-000000000-00000.
The Polycap (polypill; aspirin [acetylsalicylic acid], ramipril, simvastatin, atenolol, and hydrochlorothiazide) was found to be safe and effective for reducing multiple cardiovascular risk factors in The Indian Polycap Study (TIPS).
We evaluated the bioavailability of each ingredient of the Polycap and determined any drug-drug interactions relative to single component reference preparations.
The bioavailability of the ingredients of the Polycap (T; test) when formulated as a single capsule was compared with that of identical capsules with each of its ingredients administered separately (R; reference) in a five-arm, randomized, single-dose, two-period, two-treatment, two-sequence, crossover trial with at least a 2-week washout period in a total of 195 healthy volunteers. Plasma concentrations of each drug and, where applicable, its active metabolite were measured using validated liquid chromatography-tandem mass spectrometry and ultra-performance liquid chromatography. Mean pharmacokinetic parameters and their standard deviations were computed for each analyte.
Comparative bioavailability was computed and no drug-drug interactions and no difference in comparative bioavailability were concluded for each ingredient based on point estimates of the T/R ratio of the geometric means falling within 80-125% for peak plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC(t)), and AUC from time zero to infinity (AUC(infinity)). The T/R ratio for C(max), AUC(t) and AUC(infinity) was within 80-125% for atenolol, hydrochlorothiazide, ramipril, ramiprilat and dose-normalized salicylic acid. However, for simvastatin, the T/R point estimates for C(max), AUC(t) and AUC(infinity) for Ln-transformed data were significantly lower ( approximately 3-4%) than the lower bound of 80%. For its active metabolite, simvastatin acid, these estimates were significantly higher ( approximately 25-35%) than the higher bound of 125%. Thus, the increased bioavailability of active simvastatin acid appeared to compensate for the loss of bioavailability of simvastatin.
The Polycap was found to be effective and safe in the previously published TIPS trial. The present study in healthy volunteers establishes that Polycap is safe (no serious adverse events) and well tolerated, and that there is no indication of pharmacokinetic drug-drug interactions for any of the ingredients, with their bioavailabilities being well preserved.
在印度多药复方研究（TIPS）中，波利卡普（多药复方，即阿司匹林[乙酰水杨酸]、雷米普利、辛伐他汀、阿替洛尔和氢氯噻嗪）被发现安全有效，可降低多种心血管风险因素。
评估波利卡普中各成分的生物利用度，并确定与单一成分参考制剂相关的任何药物相互作用。
采用五臂、随机、单剂量、两周期、两治疗、两序列交叉试验设计，在 195 例健康志愿者中至少间隔 2 周洗脱期，比较波利卡普（T；试验）单胶囊制剂与各成分单独给药（R；参考）的各成分生物利用度。使用验证后的液相色谱-串联质谱法和超高效液相色谱法测量各药物的血浆浓度和（适用时）其活性代谢物。计算每个分析物的平均药代动力学参数及其标准差。
根据 T/R 比值的点估计，计算出各成分的生物等效性，且认为每个成分均无药物相互作用，且无生物等效性差异，80%-125%范围内的 T/R 比值几何均数适用于峰血浆浓度（C(max)）、从零时到最后可测量浓度的血浆浓度-时间曲线下面积（AUC(t)）和从零时到无穷大的 AUC（AUC(infinity)）。对于阿替洛尔、氢氯噻嗪、雷米普利、雷米普利拉和剂量归一化水杨酸，T/R 比值 C(max)、AUC(t)和 AUC(infinity)均在 80%-125%范围内。然而，对于辛伐他汀，C(max)、AUC(t)和 AUC(infinity)的 Ln 转换数据的 T/R 点估计值显著低于（约 3%-4%）下限 80%。对于其活性代谢物辛伐他汀酸，这些估计值显著高于（约 25%-35%）上限 125%。因此，活性辛伐他汀酸的生物利用度增加似乎弥补了辛伐他汀生物利用度的损失。
波利卡普在先前发表的 TIPS 试验中被证明是有效且安全的。本项在健康志愿者中的研究表明，波利卡普有效且安全（无严重不良事件），耐受性良好，且各成分均无药代动力学药物相互作用的迹象，其生物利用度得到很好的保留。
