Discussion
The purpose of thisstudy was to compare the PK properties to examine whether the new lisinopril/amlodipinebesylate FDC product was equivalent to the reference for a new drug application to the NMPA.In this study, the GMR and its 90% CI for the Cmax, AUC0-t, AUC0-72 (only lisinopril) and AUC0-∞ of lisinopril and amlodipinerespectively, under both fasting and fed conditions, fell within the conventional bioequivalence criteria of 0.80-1.25.In addition, compared with the reference drug, the incidence of AEs of the test drug had no difference, and showedsimilar safety and tolerance. These results indicated that the two lisinopril/amlodipinebesylate FDC preparations were bioequivalent and exchangeable in clinical practice.
In this study, food appeared to greatly decrease the extent of lisinopril absorption by more than half and affect the antihypertensive effect for both the reference and test products. These results are inconsistent with the instructions of the original lisinopril tablet (Zestril® produced by AstraZeneca UK limited) and the reference Lisonorm(produced by Gedeon Richter Ltd). The instructions say the gastrointestinal absorption of lisinopril is not affected by food.A previous study investing the influence of food consumption on the rate or extent of absorption of orally administered lisinopril in healthy volunteers observed that, a breakfast (524kcal, consisting of one fried egg, two pieces of toast or bread, 20g of orange marmalade or jelly, two stripes of bacon, 150ml of skimmed milk and 100ml of orange juice)did not affect the bioavailability of lisinopril[16]. This inconsistency may probably be due to the fact that (i) high-caloric and high-fat foods have a more obvious impact on the physiology of the gastrointestinal tract and lead to more significant changes in the bioavailability of pharmaceuticals[17]; (ii)spinach in breakfast is rich in oxalic acid, which may change gastrointestinal PH and gastrointestinal peristalsis [18]; and (iii) the participants of this study were all young Chinese adults, and there may be ethnic differences in the pharmacokinetics of lisinopril. Among ACE inhibitors, lisinopril has a unique property that does not require hydrolysis to exert ACE inhibition, and only lisinopril and captopril are not ester prodrugs and less lipophilic[19]. Food has been shown to reduce the bioavailability of captopril by 35% to 50% after a single oral administration, but not the bioavailability of inhibitors administered as ester prodrugs[20].With high solubility, low membrane permeability and poor metabolism, the pharmacokinetic of lisinopril may be dominated by absorptive transporter effects[21].Only about a quarter of the administered dose is absorbed and the low bioavailability is due to poor gastrointestinal absorption rather than first-pass hepatic metabolism, as demonstrated by the factthat mean fecal recovery of lisinopril was 69% of intact drug[22].
In order to better understand the possible reasons for the decrease of lisinopril absorption in the fed study, we searched for various factors that affect lisinopril bioavailability.Little is known about pharmacokinetic interaction of lisinopril so far.Drugs that often used with lisinopril,such as nifedipine, digoxin,hydrochlorothiazide, have no substantial effect on the pharmacokinetics of lisinopril[23-25].No drug-drug interactions (DDIs) were found between the active components amlodipine and lisinopril. One of the factors that has been reported to affect the kinetic properties of lisinopril was age. Drug concentrations of elderly patients (>65 years) have been reported to be approximately double those of younger patients[26]. And a recent study demonstrated that a concomitant ingestion of epigallocatechin gallate(EGCG)-concentrated green tea extract significantly decreased lisinopril Cmax, AUC0-24 and AUC0-∞by 71%,69% and 67%, without altering renal clearance of lisinopril[27]. However, in the present study, the enrolled subjects was all between 18 and 50 years old, and those who have drink too much tea were excluded. Moreover, it was forbidden to taketeawithin 48 hours before taking the first administration and during the test.Therefore, larger studies are needed to evaluate the effect of food on the pharmacokinetics of lisinopril in Chinese.