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.