Amlodipine bioequivalence achieved with a very sensitive liquid chromatography tandem mass spectrometric bioassay

Amlodipine (CAS 88150-42-9) is a 1,4-dihydropyridine derivative, one of the most widely used drugs for the management of essential hypertension. Tn de veloping manidipine (CAS 120092-68-4), a new antihypertensive drug, amlodip ine was selected as the reference comparator drug in a Phase III double bli nd clinical trial. However, manidipine is formulated in hard gelatin capsul es, whereas amlodipine is presented as a tablet. In order to respect the do uble blind design of the study, it was necessary to insert the amlodipine t ablet into hard gelatin capsules matching those of the new test product. Th is called for an amlodipine bioequivalence study on two halves of one table t inserted into a capsule (test formulation) and two halves of one tablet i ngested 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 c rossover design, with a wash-out period of three weeks. Plasma concentratio ns of the parent compound were monitored over a period of 6 days, consideri ng the long half-life of amlodipine. The drug was quantified with a very se nsitive, robust bioassay, which was set up and validated in our laboratory. Peak concentration and area under the curve of plasma concentrations were l og-transformed and analyzed to obtain 90 % confidence intervals which prove d 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 no t show any statistically significant difference between the test and refere nce. Both the test and reference products showed a similar and very good sa fety profile. The conclusion is that one amlodipine tablet broken into two halves and administered as such (reference formulation) is bioequivalent wi th one amlodipine tablet broken into two halves and encapsulated (test form ulation).