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.