Study design
This was a single center, randomized, open-label, single-dose,
two-period crossover bioequivalence study in both fasting and fed
conditions. According to pre-test and previous studies, the coefficient
of individual variation of lisinopril/amlodipinebesylate FDC product
arranged from 20%-30%[13-15]. Under
the condition that α=0.05, statistical test efficiency 1-β= 0.9,
coefficient of variationwas 0.28, equivalent lower limitwas 0.80, upper
limit was1.25 and actual ratiowas1, 35 samples were needed, using the
”equivalence tests for the ratio of two means in a 2x2 cross over
design” process insoftwarePower Analysis and Sample Size (PASS,version
15.0).Considering the possibility of shedding, 40 subjects were planned
to be selectedin each fasting and fed bioequivalence study. All eligible
subjects were randomly assignedaccording to the random table generated
by the statistical professionals in the Department of Shanghai Second
Military Medical University using SAS9.4. The subjects took the test(T)
and reference(R)drugsrespectivelywith 240ml water after an overnight
fast of at least 10 hours (fasting study) or after the high-fat
breakfast within half an hour before dosing(fed study).The high-fat
breakfast contained 929 kcal calories, and consisted of three pork buns
with cabbage, spinach mixed with Yuba, and
millet
gruel. Breakfast composition and energy distribution was showed in
Table1. Subjects were forbidden to drink water within 1h before and
after taking the drug, and the lunch and dinner were provided at 4 h and
8 h respectively post-drug administration. No other food and beverage
intake was permitted except the normal diets provided by the clinical
trial center during the study. A washout of 14 days was set between the
two administrations, according to the half-life recorded inoriginal drug
instructions. 4ml venous blood samples were collected before drug
administration and
at1,2,3,4,5,6,7,8,9,10,11,12,13,24,36,48,72,96,144,168h after
administration. The samples were centrifuged at 1700gear per minute for
10min at 4℃ to separate the plasma, which was divided into two
aliquots(drug monitoring at least 800ul and backup) and stored at
﹣80℃until analysis.The study flow chart is presented in Figure 1.