Amlodipine Bioequivalence Achieved with a Very Sensitive Liquid Chromatography Tandem Mass Spectrometric Bioassay

Abstract

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).

Pharmacokinetics and Bioequivalence Study of a Generic Amlodipine Tablet Formulation in Healthy Male Volunteers

“…The pharmacokinetic parameters such as C max , t max or t 1/2 were well comparable with data reported in literature after oral administration of 10 mg amlodipine. Maximum plasma concentrations of 5.5-6.7 ng/ml, time to reach maximum plasma concentrations (t max ) between 5.2-7.6 h as well as terminal plasma elimination half-lives between 34 h and 42 h were described by Marzo et al [5], Williams and Cubeddu [6] as well as Meredith and Elliott [3].…”

“…essential hypertension) and to manage coronary (i.e. angina pectoris) and ischaemic heart diseases [1][2][3][4][5].…”

“…The clinical benefit is a slow onset of action and a long duration of effect [2]. Furthermore, amlodipine is reported to be well tolerated and safe [1,4,5].…”

“…Because of the extensive distribution and slow clearance of amlodipine, the plasma elimination half-life t 1/2,ß is prolonged as compared with other calcium antagonists and was determined to be in the range of 35 h to 60 h [2,3,5].…”

The Review: The Discovery and Development of Amlodipine Drug

“…The bioequivalence test was performed on 18 healthy volunteers (9 males and 9 females). Subjects were given a single dose of 10 mg 36 .…”