Marzo A, Dal Bo L, Mazzucchelli P, Monti N C, Crivelli F, Ismaili S, Uhr M R, La Commare P
I.P.A.S. Institute for Pharmacokinetic and Analytical Studies S.A., Switzerland.
Arzneimittelforschung. 2000 Aug;50(8):688-94. doi: 10.1055/s-0031-1300274.
Amlodipine (CAS 88150-42-9) is a 1,4-dihydropyridine derivative, one of the most widely used drugs for the management of essential hypertension. In developing manidipine (CAS 120092-68-4), a new antihypertensive drug, amlodipine was selected as the reference comparator drug in a Phase III double blind clinical trial. However, manidipine is formulated in hard gelatin capsules, whereas amlodipine is presented as a tablet. In order to respect the double blind design of the study, it was necessary to insert the amlodipine tablet into hard gelatin capsules matching those of the new test product. This called for an amlodipine bioequivalence study on two halves of one tablet inserted into a capsule (test formulation) and two halves of one tablet ingested as such (reference formulation). The bioequivalence trial was carried out on 18 healthy volunteers (9 males and 9 females). Subjects were administered a single 10 mg dose of test and reference products according to a two-treatment, two-period, two-sequence crossover design, with a wash-out period of three weeks. Plasma concentrations of the parent compound were monitored over a period of 6 days, considering the long half-life of amlodipine. The drug was quantified with a very sensitive, robust bioassay, which was set up and validated in our laboratory. Peak concentration and area under the curve of plasma concentrations were log-transformed and analyzed to obtain 90% confidence intervals which proved to be 0.94-1.06, and thus within the acceptable bioequivalence range of 0.80-1.25. Time to peak, analyzed according to a non-parametric test, did not show any statistically significant difference between the test and reference. Both the test and reference products showed a similar and very good safety profile. The conclusion is that one amlodipine tablet broken into two halves and administered as such (reference formulation) is bioequivalent with one amlodipine tablet broken into two halves and encapsulated (test formulation).
氨氯地平（化学物质登记号88150 - 42 - 9）是一种1,4 - 二氢吡啶衍生物，是治疗原发性高血压最广泛使用的药物之一。在开发新型抗高血压药物马尼地平（化学物质登记号120092 - 68 - 4）时，氨氯地平在一项III期双盲临床试验中被选为参比对照药物。然而，马尼地平制成硬明胶胶囊剂型，而氨氯地平为片剂。为遵循该研究的双盲设计，有必要将氨氯地平片装入与新测试产品匹配的硬明胶胶囊中。这就需要对装入胶囊中的半片氨氯地平片（测试制剂）和直接服用的半片氨氯地平片（参比制剂）进行氨氯地平生物等效性研究。生物等效性试验在18名健康志愿者（9名男性和9名女性）身上进行。受试者按照两治疗组、两周期、两序列交叉设计，单次服用10 mg测试和参比产品，洗脱期为三周。考虑到氨氯地平的长半衰期，在6天时间内监测母体化合物的血浆浓度。采用在我们实验室建立并验证的非常灵敏、可靠的生物测定法对药物进行定量。对血浆浓度的峰浓度和曲线下面积进行对数转换并分析，以获得90%置信区间，结果为0.94 - 1.06，因此在可接受的生物等效性范围0.80 - 1.25内。根据非参数检验分析的达峰时间在测试和参比之间未显示任何统计学显著差异。测试和参比产品均显示出相似且非常良好的安全性。结论是，将一片氨氯地平片分成两半直接服用（参比制剂）与将一片氨氯地平片分成两半装入胶囊（测试制剂）具有生物等效性。
