Introduction
Hypertension is an independent and major risk factor for cardiovascular
diseases, and a lowering blood pressure (BP) substantially reduces
prematuremorbidity and
mortality[1].The 2019annual report on
cardiovascular health and diseases in China indicated that, the number
of Chinese residents withhypertensionhas reached 245
million[2]. However, only 45.8% of
the patients are treated, and the control of hypertension was
16.8%[3]. According to Chinese
Guidelines for Prevention and Treatment of Hypertension,five classes of
anti-hypertensive drugs, including calcium channel blockers (CCB),
angiotensin-converting enzyme inhibitors (ACEI), angiotensinreceptor
blockers (ARB), diuretics, β-blockers, and fixed-ratio preparations
composed of the above drugs, are recommended.Highriskgroup of patients
with BP ≥ 160/100 mmHg and 20/10mmHg higher than that of the target BP,
or patientswhoreceive mono-therapy and do not achieve the goal BPshould
be treated with combinationtherapy[4].
It is well known that, compared to free-dose combinations, fixed-dose
combinations (FDCs) of two or more antihypertensive agents in a single
pill can improve medication compliance, an importantconsideration when
requiring patients to self-administermultiple medications. One of the
preferred specific drug regimens is ACEI/CCB,as the most common adverse
effects of CCBs, peripheral edema and tachycardia, are partially
neutralized by RAAS inhibitors[5].
Lisinopril, an ACEI, can decreaseperipheral vascular resistance and
reduce blood pressure, preload, and afterload, without changes in heart
rate[6]. Lisinopril is the only ACE
inhibitor that exhibits a linear dose-response
curve[7]. The antihypertensive effect
of lisinopril usually appears within 1 h after oral administration, and
peaks at about 6h. Bioavailability of lisinopril is about 20−28 %, and
its cumulativeeffective half-lifeafter multiple administration is about
12 h. Lisinopril does not bind to other plasma proteins other thanACE,
and it is excreted from the urine in its original form without
undergoingmetabolic transformation[8].
Amlodipine, a dihydropyridine-based CCB, inhibits the transmembrane
influx of calciumions into vascular smooth muscle and is indicated for
the management of stable angina and hypertension. Amlodipine is almost
completely absorbed and is converted to inactive metabolites by CYP3A4
in liver[9].After single oral
administration, amlodipine reaches at Cmax within
6.0–8.0 hours and has a terminal elimination half-life of40–50 hours,
with high oral bioavailability of
60%–65%[10].
The combination of lisinopril and amlodipine, two classes of long acting
drugs, has a marked additional effect on blood pressure and fewer side
effects than individual monotherapy[11,
12]. Though many pharmacokinetics
studies forlisinoprilandamlodipine as a single pill have been reported,
very few were focused on an FDC.The FDC of Lisinopril 10mg/ Amlodipine
besylate 5mg (Lisonorm®) has been developed by Gedeon Richter Ltd and
approvedin multiple countriesin the European Union, but not yet in
China.The aim of this study was to compare the PK characteristics and
evaluate the bioequivalence and food effect betweenLisonorm and the
newly developed lisinopril/amlodipine besylate FDC productin Healthy
Chinese Subjects.