Discussion
This randomized, open-label, and two-period crossover studies were
firstly investigated under both fasted and fed conditions in healthy
male volunteers. In this bioequivalent study, a total of 250 volunteers
were screeded, and the baseline characteristics of all subjects were
similar regarding age and BMIs. As demonstrated in Figure 2 and
Figure 3 , the concentration-time profiles of fasting and fed states
were constant in both absorptive rates and degrees. It was observed that
gefitinib absorbs slowly and undergoes rapid plasma clearance, with the
Tmax of 4-5 hour after single administration. Moreover,
the results of the main pharmacokinetic parameters were generally
similar to those of the published literatures[10,
11].
Generally speaking, the variations of the primary pharmacokinetic
parameters (e.g., Cmax, AUC, t1/2) are
due to food-facilitated variation in physiological processes (e.g.,
gastric emptying rate, fluctuations in gastrointestinal pH, increase
luminal fluids, release of bile salts, inhibition of transporters)[12]. Besides, several literatures have reported
that CYP2D6 was associated with gefitinib exposure and may contribute to
the high inter-subject variability, but it did not influence the
bioequivalence result [13].
Undoubtedly, the property of Biopharmaceutics Classification System
(BCS) class II for gefitinib-high permeability and low solubility-may
influence the oral absorption [14]. Gefitinib
dissolves rapidly in acidic agents, but the solubilityreduces with
increasing pH until neutral pH in the intestinal tract. In the present
study, our results conclusively show higher exposure under feeding
conditions compared with studies conducted in the fasted state. In
addition, feeding conditions can alter the pH of the stomach, which can
increase dissolution and absorption by approximately 10%. Although some
literature has reported studies on the bioequivalence of gefitinib in
healthy subjects, these have shortcomings such as limited sample size
(25 cases[15], 50
cases[16]).
Besides, the range of Intra-CV was less than 22% (ranged from 10.68%
to 21.61%, Table 3) and was constant with previous literature[7, 17], which suggests that the various aspects
of quality control of this protocol are well established. The
statistical requirements were fully satisfied in the forty healthy
volunteers. Furthermore, for both formulations, rosacea, oral ulcers,
and urticaria were the most commonly reported treatment emergent adverse
event (TEAEs). The incidence of TEAEs was in agreement with what is
known for commercial formulations. [10].
It has to be admitted that there are several limitations in this study.
Firstly, according to our previous study, we partially determined the
genotypes of metabolic enzymes or transporters (e.g., CYP3A4, CYP3A5,
CYP2D6, ABCG2) that metabolize gefitinib, so we could not analyze the
variation of pharmacokinetic parameters completely[18]. Secondly, we conducted bioequivalence
studies only in healthy subjects and did not evaluate the equivalence of
T to R formulation in cancer patients. Besides, other dosage regimens
should be integrated to fully assess the comparative pharmacokinetics.