Pharmacokinetics
The mean plasma concentration versus time profiles of lisinopril and amlodipine following a single dose of the test or reference products under fasting and fed conditions are illustrated in Figure2, the PK parameters are summarized in Table3.
The intra individual variation ofAUC0-72 and AUC0-t of lisinopril were 21.2%, 19.3% and 14.5%, 13.3% respectively under fasting and fed condition, indicating that lisinopril has low variability. Therefore, the bioequivalence evaluation results ofAUC0-72 were added.
Regarding theCmax, AUC0-t, AUC0-72 (only lisinopril) and AUC0-∞ of lisinopril and amlodipine respectively,the 90% CIs for the GMRs fell within the predefined acceptance range of 80-125%, and provided supportive evidence for bioequivalence (Table4). Accordingly, lisinopril had a relatively long terminal elimination half-life of about 90 hours, which may be related to the binding saturation of the drug and ACE. In the fasting study, although the sample collected at 168 h after administration did not reach 3-5 half-lives, the last detectable concentration of all subjects was lower than 1/20 of the corresponding peak concentration and only 2.5% (2/79) of AUC_%Extrapwas more than 20%. Therefore, the plasma concentration from 0-168h can completely describe the pharmacokinetic behavior of lisinopril. Compared with the fasting study, the Cmax and AUC of lisinopril under fed condition were significantly reduced. Although 54.5% (40/74) of AUC_%Extrap was higher than 20%, 89.2% (66/74) of the final concentration at 168h were lower than 1/10 of the corresponding peak concentration, which could basically describe the pharmacokinetic behavior of lisinopril. After eliminating the data with AUC_%Extrap greater than 20% for sensitivity analysis, the 90% CI for the GMRs of AUC0-∞ of the test and reference preparation was 96.2% (86.7-106.7%).
A fat-high breakfast produced significant alteration in the Cmax and AUC of lisinopril after a dose of either reference or test drug in Chinese healthy subjects.Compared with fasting study, after high -fat postprandial administration, lisinopril Cmax, AUC0-t, AUC0-72and AUC0-∞ under fed condition were greatly decreased by 74%, 59%, 66%, 53% for test products (P<0.001), and 73%, 57%, 64%, 51% for reference products (P<0.001). In addition, there was a nearly 1.5-hour delay in median Tmax under fed conditions for the test products. However, no changes were observed in Tmaxfor reference products and in T1/2 for both the test and reference products between the two fasting and fed studies.